8-53811203-G-C

Position:

• chr8-53811203-G-C

Variant summary

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

The NM_015941.4(ATP6V1H):​c.540C>G​(p.Ser180Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP6V1H NM_015941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81

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.540C>G	p.Ser180Arg	missense_variant	7/14	ENST00000359530.7	NP_057025.2
ATP6V1H	NM_213620.3	c.540C>G	p.Ser180Arg	missense_variant	7/14		NP_998785.1
ATP6V1H	NM_213619.3	c.525+3459C>G		intron_variant			NP_998784.1
ATP6V1H	XM_006716455.4	c.525+3459C>G		intron_variant			XP_006716518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V1H	ENST00000359530.7	c.540C>G	p.Ser180Arg	missense_variant	7/14	1	NM_015941.4	ENSP00000352522.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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

Feb 15, 2023

The c.540C>G (p.S180R) alteration is located in exon 7 (coding exon 6) of the ATP6V1H gene. This alteration results from a C to G substitution at nucleotide position 540, causing the serine (S) at amino acid position 180 to be replaced by an arginine (R). 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	0.32
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.087	.;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;.;D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;L;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.37	N;N;N
REVEL	Benign	0.086
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.13	.;B;B
Vest4		0.57
MutPred		0.54		.;Loss of glycosylation at S180 (P = 0.0098);Loss of glycosylation at S180 (P = 0.0098);
MVP		0.35
MPC		0.34
ClinPred		0.64	D
GERP RS		5.4
Varity_R		0.075
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.30		Position offset: 14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-54723763;