rs550557488

Variant names:

• chr8-53743674-C-A
• rs550557488
• NM_015941.4:c.1294G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-53743674-C-A
• chr8-53743674-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015941.4(ATP6V1H):​c.1294G>T​(p.Gly432Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G432S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATP6V1H NM_015941.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.83
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015941.4. 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
	ATP6V1H	NM_015941.4	MANE Select	c.1294G>T	p.Gly432Cys	missense	Exon 13 of 14	NP_057025.2
	ATP6V1H	NM_213620.3		c.1294G>T	p.Gly432Cys	missense	Exon 13 of 14	NP_998785.1	Q9UI12-1
	ATP6V1H	NM_213619.3		c.1240G>T	p.Gly414Cys	missense	Exon 12 of 13	NP_998784.1	Q9UI12-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1H	ENST00000359530.7	TSL:1 MANE Select	c.1294G>T	p.Gly432Cys	missense	Exon 13 of 14	ENSP00000352522.2	Q9UI12-1
	ATP6V1H	ENST00000355221.7	TSL:1	c.1240G>T	p.Gly414Cys	missense	Exon 12 of 13	ENSP00000347359.3	Q9UI12-2
	ATP6V1H	ENST00000396774.6	TSL:2	c.1294G>T	p.Gly432Cys	missense	Exon 13 of 14	ENSP00000379995.2	Q9UI12-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458742 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725044

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 85942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109896

Other (OTH) AF: 0.00 AC: 0 AN: 60242

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.74
MutPred		0.53		Loss of disorder (P = 0.0419)
MVP		0.60
MPC		0.89
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.61
Mutation Taster		=15/85	disease causing

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: rs550557488; hg19: chr8-54656234;