12-53307533-C-T

Position:

chr12-53307533-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000209873.9(AAAS):c.1597G>A(p.Gly533Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,614,100 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G533E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0079 ( 20 hom., cov: 33)

Exomes 𝑓: 0.00079 ( 17 hom. )

Consequence

AAAS
ENST00000209873.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.49

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003921479).

BP6

Variant 12-53307533-C-T is Benign according to our data. Variant chr12-53307533-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 309718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00787 (1198/152284) while in subpopulation AFR AF= 0.0271 (1127/41548). AF 95% confidence interval is 0.0258. There are 20 homozygotes in gnomad4. There are 561 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AAAS	NM_015665.6 linkuse as main transcript	c.1597G>A	p.Gly533Arg	missense_variant	16/16	ENST00000209873.9	NP_056480.1
AAAS	NM_001173466.2 linkuse as main transcript	c.1498G>A	p.Gly500Arg	missense_variant	15/15		NP_001166937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AAAS	ENST00000209873.9 linkuse as main transcript	c.1597G>A	p.Gly533Arg	missense_variant	16/16	1	NM_015665.6	ENSP00000209873	P1	Q9NRG9-1

Frequencies

GnomAD3 genomes

AF:

0.00784

AC:

1193

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0271

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00353

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00480

GnomAD3 exomes

AF:

0.00194

AC:

485

AN:

250548

Hom.:

AF XY:

0.00149

AC XY:

202

AN XY:

135522

show subpopulations

Gnomad AFR exome

AF:

0.0256

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000793

AC:

1159

AN:

1461816

Hom.:

Cov.:

AF XY:

0.000668

AC XY:

486

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0271

Gnomad4 AMR exome

AF:

0.00188

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.00205

GnomAD4 genome

AF:

0.00787

AC:

1198

AN:

152284

Hom.:

Cov.:

AF XY:

0.00753

AC XY:

561

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0271

Gnomad4 AMR

AF:

0.00353

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00475

Alfa

AF:

0.00255

Hom.:

Bravo

AF:

0.00926

ESP6500AA

AF:

0.0213

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00234

AC:

284

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Glucocorticoid deficiency with achalasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.072

T;.;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.28

LIST_S2

Uncertain

0.89

D;D;D

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.55

N;.;.

MutationTaster

Benign

0.96

N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.92

N;N;N

REVEL

Benign

0.26

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.11

B;.;.

Vest4

0.41

MutPred

0.24

Gain of catalytic residue at P534 (P = 8e-04);.;.;

MVP

0.91

MPC

0.069

ClinPred

0.062

GERP RS

4.7

Varity_R

0.24

gMVP

0.32

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