NM_001690.4:c.48C>A

Variant names:

• chr3-113778801-C-A
• rs1475123226
• NM_001690.4:c.48C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001690.4(ATP6V1A):​c.48C>A​(p.Ser16Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP6V1A NM_001690.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.897

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ATP6V1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 3.3731 (above the threshold of 3.09). Trascript score misZ: 4.7152 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32430372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V1A	NM_001690.4	c.48C>A	p.Ser16Arg	missense_variant	Exon 2 of 15	ENST00000273398.8	NP_001681.2
ATP6V1A	XM_047448305.1	c.48C>A	p.Ser16Arg	missense_variant	Exon 2 of 15		XP_047304261.1
ATP6V1A	XM_047448306.1	c.48C>A	p.Ser16Arg	missense_variant	Exon 3 of 16		XP_047304262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V1A	ENST00000273398.8	c.48C>A	p.Ser16Arg	missense_variant	Exon 2 of 15	1	NM_001690.4	ENSP00000273398.3
ATP6V1A	ENST00000703904.2	c.48C>A	p.Ser16Arg	missense_variant	Exon 3 of 16			ENSP00000515542.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N;D
REVEL	Uncertain	0.44
Sift	Benign	0.035	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.0010	B;.
Vest4		0.31
MutPred		0.25		Gain of solvent accessibility (P = 0.0367);Gain of solvent accessibility (P = 0.0367);
MVP		0.72
MPC		0.87
ClinPred		0.90	D
GERP RS		2.3
Varity_R		0.26
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1475123226; hg19: chr3-113497648;