rs121918550

Positions:

chr12-53309624-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_015665.6(AAAS):c.787T>C(p.Ser263Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000762 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

AAAS
NM_015665.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 8.37

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.781

PP5

Variant 12-53309624-A-G is Pathogenic according to our data. Variant chr12-53309624-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-53309624-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AAAS	NM_015665.6 linkuse as main transcript	c.787T>C	p.Ser263Pro	missense_variant	8/16	ENST00000209873.9	NP_056480.1
AAAS	NM_001173466.2 linkuse as main transcript	c.688T>C	p.Ser230Pro	missense_variant	7/15		NP_001166937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AAAS	ENST00000209873.9 linkuse as main transcript	c.787T>C	p.Ser263Pro	missense_variant	8/16	1	NM_015665.6	ENSP00000209873	P1	Q9NRG9-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000116

AC:

AN:

249020

Hom.:

AF XY:

0.0000966

AC XY:

AN XY:

134510

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000787

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000780

AC:

114

AN:

1461388

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

726934

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000599

Gnomad4 NFE exome

AF:

0.0000693

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000311

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glucocorticoid deficiency with achalasia

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 09, 2023	Variant summary: AAAS c.787T>C (p.Ser263Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 249020 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in AAAS causing Glucocorticoid Deficiency With Achalasia (0.00012 vs 0.0011), allowing no conclusion about variant significance. c.787T>C has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Glucocorticoid Deficiency With Achalasia (example, PMID: 22538409, 18172684, 12752575). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function reporting a mislocalization of the GFP-tagged ALADIN protein to the cytosol resulting in an inhibition of the correct targeting of ALADIN to nuclear pore complex (NPC) (example, PMID: 18172684). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Pathogenic, for Achalasia-Addisonianism-Alacrima syndrome, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:11159947). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:11159947). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 02, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. This variant was detected in homozygous state. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 263 of the AAAS protein (p.Ser263Pro). This variant is present in population databases (rs121918550, gnomAD 0.07%). This missense change has been observed in individuals with achalasia-addisonianism-alacrimia syndrome, or triple A syndrome (PMID: 11159947, 22538409). It has also been observed to segregate with disease in related individuals. This variant is also known as c.869T>C. ClinVar contains an entry for this variant (Variation ID: 5045). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AAAS protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2024	Published functional studies demonstrate that mutant ALADIN protein fails to localize to the nuclear membrane (PMID: 12730363, 15666842); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20931227, 12429595, 22538409, 15666842, 11159947, 26622478, 18628786, 16098009, 1537368, 6243664, 31589614, 29255950, 18172684, 12730363, 12752575) -

Babinski sign;C0037771:Spastic paraparesis;C0151889:Hyperreflexia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 20, 2014

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2022

The c.787T>C (p.S263P) alteration is located in coding exon 8 of the AAAS gene. This alteration results from a T to C substitution at nucleotide position 787, causing the serine (S) at amino acid position 263 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.01% (34/280414) total alleles studied. The highest observed frequency was 0.07% (18/25078) of European (Finnish) alleles. The p.S263P mutation has been reported in the homozygous and compound heterozygous states in multiple unrelated patients with triple A syndrome (Handschug, 2001; Prpic, 2003; Milenkovi, 2008; Dumic, 2012; Dumic, 2016; Kurnaz, 2018; internal data). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies demonstrated protein mislocalization in transfected HeLa cells and patient fibroblasts (Milenkovi, 2008; Jühlen, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;.;.;T;T

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.68

T;T;T;T;T

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.78

D;D;D;D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

4.1

H;.;.;.;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-4.1

D;D;D;D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.017

D;D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;.;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.97

MVP

0.93

MPC

0.41

ClinPred

0.98

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.80

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over