Variant 7-73671141-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001077621.2(VPS37D):c.521G>A(p.Arg174His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000874 in 1,607,114 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00093 ( 2 hom. )

Consequence

VPS37D
NM_001077621.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.962

Variant links:

Genes affected

VPS37D (HGNC:18287): (VPS37D subunit of ESCRT-I) Predicted to be involved in protein targeting to membrane; protein targeting to vacuole; and ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway. Located in extracellular exosome. Part of ESCRT I complex. [provided by Alliance of Genome Resources, Apr 2022]

VPS37D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07565799).

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VPS37D	NM_001077621.2 linkuse as main transcript	c.521G>A	p.Arg174His	missense_variant	4/4	ENST00000324941.5	NP_001071089.1
VPS37D	XM_017011779.2 linkuse as main transcript	c.398G>A	p.Arg133His	missense_variant	4/4		XP_016867268.1
VPS37D	XM_047419927.1 linkuse as main transcript	c.293G>A	p.Arg98His	missense_variant	4/4		XP_047275883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS37D	ENST00000324941.5 linkuse as main transcript	c.521G>A	p.Arg174His	missense_variant	4/4	1	NM_001077621.2	ENSP00000320416	P1
VPS37D	ENST00000451519.1 linkuse as main transcript	c.266G>A	p.Arg89His	missense_variant	2/2	5		ENSP00000413337

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000317

AC:

AN:

230214

Hom.:

AF XY:

0.000330

AC XY:

AN XY:

127314

show subpopulations

Gnomad AFR exome

AF:

0.000303

Gnomad AMR exome

AF:

0.0000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000115

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000640

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000925

AC:

1346

AN:

1454920

Hom.:

Cov.:

AF XY:

0.000910

AC XY:

659

AN XY:

723886

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00118

Gnomad4 OTH exome

AF:

0.000433

GnomAD4 genome

AF:

0.000388

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000720

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000589

Hom.:

Bravo

AF:

0.000370

ExAC

AF:

0.000195

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2023

The c.521G>A (p.R174H) alteration is located in exon 4 (coding exon 4) of the VPS37D gene. This alteration results from a G to A substitution at nucleotide position 521, causing the arginine (R) at amino acid position 174 to be replaced by a histidine (H). 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

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.065

T;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.068

MetaRNN

Benign

0.076

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.97

L;.

MutationTaster

Benign

0.65

N;N

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.4

N;D

REVEL

Benign

0.057

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

0.99

D;.

Vest4

0.14

MVP

0.13

MPC

0.53

ClinPred

0.045

GERP RS

3.0

Varity_R

0.11

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over