12-53321423-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_015665.6(AAAS):c.43C>A(p.Gln15Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q15Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

AAAS
NM_015665.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14U:1

Conservation

PhyloP100: 2.63

Publications

21 publications found

Variant links:

Genes affected

AAAS (HGNC:13666): (aladin WD repeat nucleoporin) The protein encoded by this gene is a member of the WD-repeat family of regulatory proteins and may be involved in normal development of the peripheral and central nervous system. The encoded protein is part of the nuclear pore complex and is anchored there by NDC1. Defects in this gene are a cause of achalasia-addisonianism-alacrima syndrome (AAAS), also called triple-A syndrome or Allgrove syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

AAAS Gene-Disease associations (from GenCC):

triple-A syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

AAAS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 12-53321423-G-T is Pathogenic according to our data. Variant chr12-53321423-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AAAS	NM_015665.6 link	c.43C>A	p.Gln15Lys	missense_variant	Exon 1 of 16	ENST00000209873.9	NP_056480.1
AAAS	NM_001173466.2 link	c.43C>A	p.Gln15Lys	missense_variant	Exon 1 of 15		NP_001166937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AAAS	ENST00000209873.9 link	c.43C>A	p.Gln15Lys	missense_variant	Exon 1 of 16	1	NM_015665.6	ENSP00000209873.4

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000183

AC:

AN:

251366

AF XY:

0.000213

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000163

AC:

239

AN:

1461856

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

126

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000533

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000163

AC:

181

AN:

1112008

Other (OTH)

AF:

0.0000828

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000125

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41476

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000910

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000231

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glucocorticoid deficiency with achalasia

Pathogenic:8Uncertain:1

Nov 01, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 23, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: AAAS c.43C>A (p.Gln15Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic exonic 5' splice donor site located at nucleotide 41. At least one publication reports experimental evidence that this variant affects mRNA splicing due to the activation of the cryptic exonic splice donor site resulting in a frame shifted protein referred to as p.G14Vfs*45 (Krumbholz_2006). The variant allele was found at a frequency of 0.00018 in 251366 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in AAAS causing Glucocorticoid Deficiency With Achalasia (0.00018 vs 0.0011), allowing no conclusion about variant significance. c.43C>A has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with features of Glucocorticoid Deficiency With Achalasia (also referred to as AAA syndrome) (example, Handschug_2001, Houlden_2002, Dumic_2012, Krumbholz_2006). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic, n=5; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 14, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Across a selection of available literature, the AAAS c.43C>A (p.Gln15Lys) missense variant (also referred to as p.Gly14ValfsTer45) has been reported in a homozygous state in at least six individuals with achalasia-Addisonianism-alacrima syndrome (which is also referred to as triple A syndrome), and in a compound heterozygous state in at least three other affected families (Handschug et al. 2001; Sandrini et al. 2001; Houlden et al. 2002; Huebner et al. 2004; Strauss et al. 2008; Dumic et al, 2012). In at least two families who were compound heterozygous for this variant, parents were shown to be heterozygous carriers of the p.Gln15Lys variant. This variant was absent from at least 50 controls but is reported at a frequency of 0.000606 in the South Asian population from the Exome Aggregation Consortium. In fibroblasts from a patient heterozygous for the p.Gln15Lys variant, Krumbholz et al. (2006) observed two splice products after amplification from a forward primer in exon 1 and reverse primer in exon 2. They conclude that the c.43C>A variant creates a novel splice donor site resulting in a frameshift and premature truncation of the protein (referred to as p.Gly14ValfsTer45). Based on the collective evidence, the p.Gln15Lys variant is classified as pathogenic for achalasia-Addisonianism-alacrima syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Oct 19, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant c.43C>A p.Gln15Lys in the AAAS gene has been reported previously in heterozygous and homozygous state in individuals affected with Triple A Allgrove syndrome. In a study, they concluded that the c.43C>A variant creates a novel splice donor site resulting in a frameshift and premature truncation of the protein referred to as p.Gly14ValfsTer45 Jayant et al., 2021; Krumbholz et al., 2006. This variant is reported with the allele frequency 0.01% in the gnomAD. It is submitted to ClinVar with varying interpretations as Uncertain significance/ Pathogenic multiple submitters. The amino acid Gln at position 15 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence Polyphen, SIFT and MutationTaster predicts conflicting evidence on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. -

Aug 15, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Sep 26, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Mar 15, 2019

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The observed variant NM_015665.6:c.43C>A/p.Gln15Lys is a missense variation found in exon 1 of the AAAS gene. It is a known pathogenic variant (dbsnp: rs121918549) and has been reported in the ExAC and gnomAD database with an allele frequency of 0.0002317 and 0.0191, respectively. The in silico prediction of this variant is disease causing by MutationTaster2. Parents of this patients are heterozygote carriers of this mutation. In summary, this variant meets the ACMG criteria to be classified as pathogenic based upon the evidence stated above. -

not provided

Pathogenic:4

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 15 of the AAAS protein (p.Gln15Lys). This variant is present in population databases (rs121918549, gnomAD 0.06%). This missense change has been observed in individual(s) with achalasia-addisonianism-alacrimia syndrome (PMID: 11159947, 22538409, 32146693). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5044). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt AAAS protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Oct 27, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1, PP4, PM1, PM2, PM3_strong, PS3, PS4 -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 05, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate activation of a cryptic splice donor site that results in a frameshift at codon Glycine 14, changes this to a Valine residue, and creates a premature Stop codon at position 45 of the new reading frame (Krumbholz et al., 2006); also reported as p.Gly14ValfsX45; Variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11159947, 28655339, 15666842, 12730363, 22538409, 12429595, 18615337, 15217518, 11701718, 26622478, 18628786, 32185032, 31589614, 34426522, 32146693, 23073554, 16609705) -

Inborn genetic diseases

Pathogenic:1

Oct 18, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.43C>A (p.Q15K) alteration is located in exon 1 (coding exon 1) of the AAAS gene. This alteration results from a C to A substitution at nucleotide position 43, causing the glutamine (Q) at amino acid position 15 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.017% (47/282768) total alleles studied. The highest observed frequency was 0.056% (17/30616) of South Asian alleles. This variant (also referred to as p.G14Vfs*45) has been identified in the homozygous state and in conjunction with other AAAS variants in multiple individuals with features consistent with triple A syndrome; in at least one instance, the variants were identified in trans (Jayant, 2021; Ulgiati, 2021; Zheng, 2020; Lorea, 2020; Vezzoli, 2020; Ganapathy, 2019; Zhang, 2017; Vallet, 2012; Dumic, 2012; Huebner, 2004). This nucleotide position is not well conserved in available vertebrate species. RNA studies have demonstrated that this alteration results in abnormal splicing (Krumbholz, 2006). The in silico prediction for this alteration is inconclusive. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

AAAS-related disorder

Pathogenic:1

Sep 10, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The AAAS c.43C>A variant is predicted to result in the amino acid substitution p.Gln15Lys. This variant has been reported in the homozygous or compound heterozygous state in individuals with Triple-A syndrome (see, for example, Sandrini et al. 2001. PubMed ID: 11701718; reported as Q15K in Handschug et al. 2001. PubMed ID: 11159947; Table S1, Ganapathy et al. 2019. PubMed ID: 31069529; Jayant et al. 2021. PubMed ID: 32700293; Houlden et al. 2002. PubMed ID: 12429595; Papageorgiou et al 2013. PubMed ID: 23073554). This variant is reported in 0.056% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.090

T;.;T

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.64

T;T;T

M_CAP

Benign

0.078

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

0.81

L;L;.

PhyloP100

2.6

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.83

N;N;N

REVEL

Uncertain

0.50

Sift

Benign

0.71

T;T;T

Sift4G

Benign

0.93

T;T;.

Polyphen

0.78

P;.;.

Vest4

0.73

MVP

0.84

MPC

0.085

ClinPred

0.16

GERP RS

4.2

PromoterAI

0.047

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.47

gMVP

0.59

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.92

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.92

Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over