3-113781071-C-T

Variant names:

• chr3-113781071-C-T
• rs367827756
• NM_001690.4:c.104C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_001690.4(ATP6V1A):​c.104C>T​(p.Ala35Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000827 in 1,450,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A35A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: ATP6V1A NM_001690.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.36
• Publications: 3 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: Uncertain_significance. The variant received 1 ACMG points.

• 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 2D, developmental and epileptic encephalopathy 93, autosomal recessive cutis laxa type 2, classic type, undetermined early-onset epileptic encephalopathy.

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.104C>T	p.Ala35Val	missense	Exon 3 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.104C>T	p.Ala35Val	missense	Exon 3 of 15	ENSP00000273398.3	P38606-1
	ATP6V1A	ENST00000703904.2		c.104C>T	p.Ala35Val	missense	Exon 4 of 16	ENSP00000515542.1	P38606-1
	ATP6V1A	ENST00000703910.1		c.104C>T	p.Ala35Val	missense	Exon 4 of 16	ENSP00000515547.1	P38606-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000417 AC: 1 AN: 239936 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000926

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000827 AC: 12 AN: 1450530 Hom.: 0 Cov.: 30 AF XY: 0.00000693 AC XY: 5 AN XY: 721328

African (AFR) AF: 0.00 AC: 0 AN: 33200

American (AMR) AF: 0.00 AC: 0 AN: 43162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25218

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 84778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000994 AC: 11 AN: 1106110

Other (OTH) AF: 0.0000167 AC: 1 AN: 59870

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.38
Sift	Benign	0.21	T
Sift4G	Benign	0.27	T
Polyphen		0.49	P
Vest4		0.52
MVP		0.36
MPC		0.95
ClinPred		0.84	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.28
gMVP		0.68
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs367827756; hg19: chr3-113499918; COSMIC: COSV56365231; COSMIC: COSV56365231;