Variant chr7-73667969-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001077621.2(VPS37D):c.11C>T(p.Ala4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000078 in 1,063,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000055 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

VPS37D
NM_001077621.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.104

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.029982477).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS37D	NM_001077621.2 linkuse as main transcript	c.11C>T	p.Ala4Val	missense_variant	1/4	ENST00000324941.5	NP_001071089.1	Q86XT2
VPS37D	XM_017011779.2 linkuse as main transcript	c.16-1450C>T		intron_variant			XP_016867268.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS37D	ENST00000324941.5 linkuse as main transcript	c.11C>T	p.Ala4Val	missense_variant	1/4	1	NM_001077621.2	ENSP00000320416.4		Q86XT2
VPS37D	ENST00000451519.1 linkuse as main transcript	c.11C>T	p.Ala4Val	missense_variant	1/2	5		ENSP00000413337.1		C9JYT9

Frequencies

GnomAD3 genomes

AF:

0.0000549

AC:

AN:

145820

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000676

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000915

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000450

AC:

AN:

2220

Hom.:

AF XY:

0.00

AC XY:

AN XY:

1164

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00254

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000817

AC:

AN:

917990

Hom.:

Cov.:

AF XY:

0.0000856

AC XY:

AN XY:

432300

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000158

Gnomad4 NFE exome

AF:

0.0000859

Gnomad4 OTH exome

AF:

0.0000312

GnomAD4 genome

AF:

0.0000549

AC:

AN:

145820

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

70972

show subpopulations

Gnomad4 AFR

AF:

0.0000249

Gnomad4 AMR

AF:

0.0000676

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000915

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000642

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

Dec 13, 2022

The c.11C>T (p.A4V) alteration is located in exon 1 (coding exon 1) of the VPS37D gene. This alteration results from a C to T substitution at nucleotide position 11, causing the alanine (A) at amino acid position 4 to be replaced by a valine (V). 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

Pathogenic

0.60

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.023

T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.59

T;T

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.030

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

0.99

N;N

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.48

N;N

REVEL

Benign

0.075

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.25

T;T

Polyphen

0.81

P;.

Vest4

0.10

MVP

0.043

MPC

1.9

ClinPred

0.19

GERP RS

1.7

Varity_R

0.19

gMVP

0.33

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