chr3-185044536-T-C

Variant names:

• chr3-185044536-T-C
• rs6765837
• NM_001009921.3:c.4057-3943T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001009921.3(VPS8):​c.4057-3943T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 151,748 control chromosomes in the GnomAD database, including 25,164 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.57 (25164 hom., cov: 30)
• Consequence: VPS8 NM_001009921.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.291
• Publications: 5 publications found

Genes affected

VPS8 (HGNC:29122): (VPS8 subunit of CORVET complex) Predicted to enable metal ion binding activity. Involved in endosomal vesicle fusion. Located in early endosome. [provided by Alliance of Genome Resources, Apr 2022]

VPS8 Gene-Disease associations (from GenCC):

• arthrogryposis multiplex congenita

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS8	NM_001009921.3	c.4057-3943T>C		intron_variant	Intron 46 of 47	ENST00000625842.3	NP_001009921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS8	ENST00000625842.3	c.4057-3943T>C		intron_variant	Intron 46 of 47	5	NM_001009921.3	ENSP00000487164.1

Frequencies

GnomAD3 genomes AF: 0.567 AC: 85943 AN: 151630 Hom.: 25130 Cov.: 30

Gnomad AFR AF: 0.698

Gnomad AMI AF: 0.574

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.383

Gnomad EAS AF: 0.689

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.481

Gnomad OTH AF: 0.526

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

GnomAD4 genome AF: 0.567 AC: 86032 AN: 151748 Hom.: 25164 Cov.: 30 AF XY: 0.574 AC XY: 42557 AN XY: 74102

African (AFR) AF: 0.698 AC: 28880 AN: 41388

American (AMR) AF: 0.562 AC: 8580 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 1328 AN: 3470

East Asian (EAS) AF: 0.690 AC: 3540 AN: 5132

South Asian (SAS) AF: 0.664 AC: 3174 AN: 4778

European-Finnish (FIN) AF: 0.581 AC: 6106 AN: 10510

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.481 AC: 32671 AN: 67904

Other (OTH) AF: 0.525 AC: 1107 AN: 2108

Alfa AF: 0.492 Hom.: 30373

Bravo AF: 0.567

Asia WGS AF: 0.652 AC: 2265 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.1
DANN	Benign	0.24
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

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: rs6765837; hg19: chr3-184762324;