rs1060505037

Positions:

• chr3-113784227-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_001690.4(ATP6V1A):​c.215G>A​(p.Gly72Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP6V1A NM_001690.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.33

Genes affected

ATP6V1A (HGNC:851): (ATPase H+ transporting V1 subunit A) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c", and d. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This encoded protein is one of two V1 domain A subunit isoforms and is found in all tissues. Transcript variants derived from alternative polyadenylation exist. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP6V1A. . Gene score misZ 3.3731 (greater than the threshold 3.09). Trascript score misZ 4.7152 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive cutis laxa type 2, classic type, undetermined early-onset epileptic encephalopathy, epileptic encephalopathy, infantile or early childhood, 3, autosomal recessive cutis laxa type 2D.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 3-113784227-G-A is Pathogenic according to our data. Variant chr3-113784227-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 417773.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-113784227-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V1A	NM_001690.4	c.215G>A	p.Gly72Asp	missense_variant	4/15	ENST00000273398.8	NP_001681.2
ATP6V1A	XM_047448305.1	c.215G>A	p.Gly72Asp	missense_variant	4/15		XP_047304261.1
ATP6V1A	XM_047448306.1	c.215G>A	p.Gly72Asp	missense_variant	5/16		XP_047304262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V1A	ENST00000273398.8	c.215G>A	p.Gly72Asp	missense_variant	4/15	1	NM_001690.4	ENSP00000273398	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive cutis laxa type 2D Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 27, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;T;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.97
MutPred		0.77		Loss of glycosylation at S71 (P = 0.0335);.;Loss of glycosylation at S71 (P = 0.0335);
MVP		0.92
MPC		2.0
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1060505037; hg19: chr3-113503074; COSMIC: COSV56362133;