8-53756608-AGC-GGT

Variant names:

• chr8-53756608-AGC-GGT
• NM_015941.4:c.1222_1224delGCTinsACC
• ATP6V1H p.Ala408Thr

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_015941.4(ATP6V1H):​c.1222_1224delGCTinsACC​(p.Ala408Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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. A408S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP6V1H NM_015941.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• 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 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1222_1224delGCTinsACC	p.Ala408Thr	missense	N/A	NP_057025.2
	ATP6V1H	NM_213620.3		c.1222_1224delGCTinsACC	p.Ala408Thr	missense	N/A	NP_998785.1	Q9UI12-1
	ATP6V1H	NM_213619.3		c.1168_1170delGCTinsACC	p.Ala390Thr	missense	N/A	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.1222_1224delGCTinsACC	p.Ala408Thr	missense	N/A	ENSP00000352522.2	Q9UI12-1
	ATP6V1H	ENST00000355221.7	TSL:1	c.1168_1170delGCTinsACC	p.Ala390Thr	missense	N/A	ENSP00000347359.3	Q9UI12-2
	ATP6V1H	ENST00000396774.6	TSL:2	c.1222_1224delGCTinsACC	p.Ala408Thr	missense	N/A	ENSP00000379995.2	Q9UI12-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr8-54669168;