12-53307573-A-G

Position:

• chr12-53307573-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000209873.9(AAAS):​c.1557T>C​(p.Thr519=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 1,614,170 control chromosomes in the GnomAD database, including 171 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (96 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (75 hom.)
• Consequence: AAAS ENST00000209873.9 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.29

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015183389).
• BP6: Variant 12-53307573-A-G is Benign according to our data. Variant chr12-53307573-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 309721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AAAS	NM_015665.6	c.1557T>C	p.Thr519=	synonymous_variant	16/16	ENST00000209873.9	NP_056480.1
AAAS	NM_001173466.2	c.1458T>C	p.Thr486=	synonymous_variant	15/15		NP_001166937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AAAS	ENST00000209873.9	c.1557T>C	p.Thr519=	synonymous_variant	16/16	1	NM_015665.6	ENSP00000209873	P1

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2841 AN: 152212 Hom.: 95 Cov.: 33

Gnomad AFR AF: 0.0656

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00479 AC: 1203 AN: 251168 Hom.: 33 AF XY: 0.00334 AC XY: 454 AN XY: 135796

Gnomad AFR exome AF: 0.0680

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00188 AC: 2755 AN: 1461840 Hom.: 75 Cov.: 34 AF XY: 0.00162 AC XY: 1178 AN XY: 727214

Gnomad4 AFR exome AF: 0.0697

Gnomad4 AMR exome AF: 0.00304

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.00397

GnomAD4 genome AF: 0.0187 AC: 2851 AN: 152330 Hom.: 96 Cov.: 33 AF XY: 0.0181 AC XY: 1348 AN XY: 74498

Gnomad4 AFR AF: 0.0657

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00972 Hom.: 19

Bravo AF: 0.0220

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0749 AC: 330

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00600 AC: 729

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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	- -

AAAS-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	3.0
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0015	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	0.40	N
Sift	Uncertain	0.023	D
MVP		0.88
GERP RS		-9.4

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

Other links and lift over

dbSNP: rs112987708; hg19: chr12-53701357;