rs878853277

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV006582785: Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID:27231034)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 24)
• Consequence: ATP6AP1 NM_001183.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.90
• Publications: 14 publications found

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]

ATP6AP1 Gene-Disease associations (from GenCC):

• congenital disorder of glycosylation type II

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• immunodeficiency 47

  Inheritance: XL Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV006582785: Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 27231034).; SCV001783130: Published functional studies demonstrate a reduction in V-ATPase function and cellular growth (Jansen et al., 2016)
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 236241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001183.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP1	NM_001183.6	MANE Select	c.1036G>A	p.Glu346Lys	missense	Exon 9 of 10	NP_001174.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP1	ENST00000369762.7	TSL:1 MANE Select	c.1036G>A	p.Glu346Lys	missense	Exon 9 of 10	ENSP00000358777.2	Q15904
	ATP6AP1	ENST00000619046.5	TSL:1	c.652G>A	p.Glu218Lys	missense	Exon 8 of 9	ENSP00000482243.2	A0A0C4DGX8
	ATP6AP1	ENST00000945275.1		c.1108G>A	p.Glu370Lys	missense	Exon 10 of 11	ENSP00000615334.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Immunodeficiency 47 (3)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.9
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.033	D
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
Mutation Taster		=27/73	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs878853277; hg19: chrX-153663684; COSMIC: COSV63895463; COSMIC: COSV63895463;