NM_001183.6:c.1036G>A

Variant names:

• chrX-154435338-G-A
• rs878853277
• NM_001183.6:c.1036G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001183.6(ATP6AP1):​c.1036G>A​(p.Glu346Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: ATP6AP1 NM_001183.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.90

Genes affected

ATP6AP1 (HGNC:868): (ATPase H+ transporting accessory protein 1) This gene encodes a component of a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. Vacuolar ATPase (V-ATPase) is comprised of a cytosolic V1 (site of the ATP catalytic site) and a transmembrane V0 domain. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, and receptor-mediated endocytosis. The encoded protein of this gene may assist in the V-ATPase-mediated acidification of neuroendocrine secretory granules. This protein may also play a role in early development. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154435338-G-A is Pathogenic according to our data. Variant chrX-154435338-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 236241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154435338-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6AP1	NM_001183.6	c.1036G>A	p.Glu346Lys	missense_variant	Exon 9 of 10	ENST00000369762.7	NP_001174.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6AP1	ENST00000369762.7	c.1036G>A	p.Glu346Lys	missense_variant	Exon 9 of 10	1	NM_001183.6	ENSP00000358777.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 47 Pathogenic:2

Dec 23, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 moderate, PM2 moderate, PP1 moderate, BP4 supporting -

May 28, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Jun 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 346 of the ATP6AP1 protein (p.Glu346Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ATP6AP1 deficiency (PMID: 27231034, 34621841). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236241). 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 not expected to disrupt ATP6AP1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Mar 19, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a reduction in V-ATPase function and cellular growth (Jansen et al., 2016); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27231034) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T;T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.7	M;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	D;N;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.018	D;T;.
Sift4G	Uncertain	0.033	D;D;T
Polyphen		0.99	D;.;.
Vest4		0.78
MutPred		0.62		Gain of MoRF binding (P = 0.0174);.;.;
MVP		0.33
MPC		0.95
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.91
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs878853277; hg19: chrX-153663684; COSMIC: COSV63895463; COSMIC: COSV63895463;