8-17274932-A-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_152415.3(VPS37A):c.616A>T(p.Ile206Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,614,096 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 8 hom., cov: 32)

Exomes 𝑓: 0.011 ( 106 hom. )

Consequence

VPS37A
NM_152415.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.10

Variant links:

Genes affected

VPS37A (HGNC:24928): (VPS37A subunit of ESCRT-I) This gene belongs to the VPS37 family, and encodes a component of the ESCRT-I (endosomal sorting complex required for transport I) protein complex, required for the sorting of ubiquitinated transmembrane proteins into internal vesicles of multivesicular bodies. Expression of this gene is downregulated in hepatocellular carcinoma, and mutations in this gene are associated with autosomal recessive spastic paraplegia-53. A related pseudogene has been identified on chromosome 5. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2012]

VPS37A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00709638).

BP6

Variant 8-17274932-A-T is Benign according to our data. Variant chr8-17274932-A-T is described in ClinVar as [Benign]. Clinvar id is 383980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS37A	NM_152415.3 link	c.616A>T	p.Ile206Phe	missense_variant	Exon 5 of 12	ENST00000324849.9	NP_689628.2	Q8NEZ2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS37A	ENST00000324849.9 link	c.616A>T	p.Ile206Phe	missense_variant	Exon 5 of 12	1	NM_152415.3	ENSP00000318629.4		Q8NEZ2-1

Frequencies

GnomAD3 genomes

AF:

0.00793

AC:

1206

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00191

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0108

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0103

Gnomad FIN

AF:

0.00640

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0112

Gnomad OTH

AF:

0.00862

GnomAD3 exomes

AF:

0.00836

AC:

2101

AN:

251350

Hom.:

AF XY:

0.00903

AC XY:

1226

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00596

Gnomad ASJ exome

AF:

0.00943

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0101

Gnomad FIN exome

AF:

0.00532

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.0105

AC:

15410

AN:

1461822

Hom.:

106

Cov.:

AF XY:

0.0105

AC XY:

7639

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00215

Gnomad4 AMR exome

AF:

0.00695

Gnomad4 ASJ exome

AF:

0.00930

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00974

Gnomad4 FIN exome

AF:

0.00577

Gnomad4 NFE exome

AF:

0.0116

Gnomad4 OTH exome

AF:

0.00984

GnomAD4 genome

AF:

0.00793

AC:

1208

AN:

152274

Hom.:

Cov.:

AF XY:

0.00772

AC XY:

575

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00190

Gnomad4 AMR

AF:

0.0108

Gnomad4 ASJ

AF:

0.00836

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0108

Gnomad4 FIN

AF:

0.00640

Gnomad4 NFE

AF:

0.0112

Gnomad4 OTH

AF:

0.00806

Alfa

AF:

0.00947

Hom.:

Bravo

AF:

0.00791

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0143

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0114

AC:

ExAC

AF:

0.00836

AC:

1015

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0113

EpiControl

AF:

0.0132

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VPS37A: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Jul 11, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary spastic paraplegia 53

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Dec 20, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.042

T;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.83

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.0071

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.053

Sift

Uncertain

0.013

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.034

B;B

Vest4

0.22

MVP

0.082

MPC

0.015

ClinPred

0.0059

GERP RS

0.28

Varity_R

0.067

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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