12-53308975-T-TA

Position:

• chr12-53308975-T-TA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The ENST00000209873.9(AAAS):​c.980_981insT​(p.Ser328IlefsTer37) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L327L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AAAS ENST00000209873.9 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.27

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-53308975-T-TA is Pathogenic according to our data. Variant chr12-53308975-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 5041.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AAAS	NM_015665.6	c.980_981insT	p.Ser328IlefsTer37	frameshift_variant	10/16	ENST00000209873.9	NP_056480.1
AAAS	NM_001173466.2	c.881_882insT	p.Ser295IlefsTer37	frameshift_variant	9/15		NP_001166937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AAAS	ENST00000209873.9	c.980_981insT	p.Ser328IlefsTer37	frameshift_variant	10/16	1	NM_015665.6	ENSP00000209873	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Glucocorticoid deficiency with achalasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs387906326; hg19: chr12-53702759;