3-113778783-C-A

Variant names:

• chr3-113778783-C-A
• rs1708946008
• NM_001690.4:c.30C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_001690.4(ATP6V1A):​c.30C>A​(p.Leu10Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,441,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L10L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATP6V1A NM_001690.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.434
• Publications: 0 publications found

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]

ATP6V1A Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy 93

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive cutis laxa type 2D

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive cutis laxa type 2, classic type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP7: Synonymous conserved (PhyloP=-0.434 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001690.4. 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
	ATP6V1A	NM_001690.4	MANE Select	c.30C>A	p.Leu10Leu	synonymous	Exon 2 of 15	NP_001681.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1A	ENST00000273398.8	TSL:1 MANE Select	c.30C>A	p.Leu10Leu	synonymous	Exon 2 of 15	ENSP00000273398.3	P38606-1
	ATP6V1A	ENST00000703904.2		c.30C>A	p.Leu10Leu	synonymous	Exon 3 of 16	ENSP00000515542.1	P38606-1
	ATP6V1A	ENST00000703910.1		c.30C>A	p.Leu10Leu	synonymous	Exon 3 of 16	ENSP00000515547.1	P38606-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441754 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 717118

African (AFR) AF: 0.00 AC: 0 AN: 32694

American (AMR) AF: 0.00 AC: 0 AN: 42572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25654

East Asian (EAS) AF: 0.00 AC: 0 AN: 38416

South Asian (SAS) AF: 0.00 AC: 0 AN: 82300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5448

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102514

Other (OTH) AF: 0.00 AC: 0 AN: 59338

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	2.0
DANN	Benign	0.69
PhyloP100		-0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs1708946008; hg19: chr3-113497630;