chr8-53829452-T-C

Position:

• chr8-53829452-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000359530.7(ATP6V1H):​c.298A>G​(p.Met100Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP6V1H ENST00000359530.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16

Genes affected

ATP6V1H (HGNC:18303): (ATPase H+ transporting V1 subunit H) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular organelles. V-ATPase-dependent organelle acidification is necessary for multiple processes including protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. The encoded protein is the regulatory H subunit of the V1 domain of V-ATPase, which is required for catalysis of ATP but not the assembly of V-ATPase. Decreased expression of this gene may play a role in the development of type 2 diabetes. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V1H	NM_015941.4	c.298A>G	p.Met100Val	missense_variant	4/14	ENST00000359530.7	NP_057025.2
ATP6V1H	NM_213620.3	c.298A>G	p.Met100Val	missense_variant	4/14		NP_998785.1
ATP6V1H	NM_213619.3	c.298A>G	p.Met100Val	missense_variant	4/13		NP_998784.1
ATP6V1H	XM_006716455.4	c.298A>G	p.Met100Val	missense_variant	4/13		XP_006716518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V1H	ENST00000359530.7	c.298A>G	p.Met100Val	missense_variant	4/14	1	NM_015941.4	ENSP00000352522

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2024

The c.298A>G (p.M100V) alteration is located in exon 4 (coding exon 3) of the ATP6V1H gene. This alteration results from a A to G substitution at nucleotide position 298, causing the methionine (M) at amino acid position 100 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	.;.;T;T;T;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D;.;D;T;T
M_CAP	Benign	0.0058	T
MetaRNN	Uncertain	0.48	T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	2.0	M;.;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0080	D;D;D;D;D;D
Sift4G	Benign	0.18	T;T;T;T;T;.
Polyphen		0.063	B;.;B;B;.;.
Vest4		0.36
MutPred		0.65		Loss of disorder (P = 0.1745);.;Loss of disorder (P = 0.1745);Loss of disorder (P = 0.1745);Loss of disorder (P = 0.1745);Loss of disorder (P = 0.1745);
MVP		0.28
MPC		0.26
ClinPred		0.69	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.35
gMVP		0.39

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: rs1297964597; hg19: chr8-54742012;