rs878853277

Positions:

• chrX-154435338-G-A

Variant summary

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

The ENST00000369762.7(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 ENST00000369762.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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/exons	MANE	Protein	UniProt
ATP6AP1	NM_001183.6	c.1036G>A	p.Glu346Lys	missense_variant	9/10	ENST00000369762.7	NP_001174.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6AP1	ENST00000369762.7	c.1036G>A	p.Glu346Lys	missense_variant	9/10	1	NM_001183.6	ENSP00000358777	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 47 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 28, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 23, 2021	ACMG classification criteria: PS3 supporting, PS4 moderate, PM2 moderate, PP1 moderate, BP4 supporting -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 19, 2019

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;.;.
MutationTaster	Benign	0.96	D
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;