Genetic Variant VPS37B:p.Arg206His (chr12-122867357-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_024667.3(VPS37B):c.617G>A(p.Arg206His) variant causes a missense change. The variant allele was found at a frequency of 0.000833 in 1,591,998 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00052 ( 0 hom., cov: 22)

Exomes 𝑓: 0.00086 ( 0 hom. )

Consequence

VPS37B
NM_024667.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.24

Variant links:

Genes affected

VPS37B (HGNC:25754): (VPS37B subunit of ESCRT-I) Enables calcium-dependent protein binding activity. Involved in positive regulation of viral budding via host ESCRT complex. Located in endosome membrane; midbody; and plasma membrane. Part of ESCRT I complex. [provided by Alliance of Genome Resources, Apr 2022]

VPS37B 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=0.034998238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS37B	NM_024667.3 link	c.617G>A	p.Arg206His	missense_variant	Exon 4 of 4	ENST00000267202.7	NP_078943.1	Q9H9H4A0A024RBU0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VPS37B	ENST00000267202.7 link	c.617G>A	p.Arg206His	missense_variant	Exon 4 of 4	1	NM_024667.3	ENSP00000267202.2	Q9H9H4
VPS37B	ENST00000535765.5 link	c.611G>A	p.Arg204His	missense_variant	Exon 4 of 4	3		ENSP00000446075.1	F5H4M0
VPS37B	ENST00000371248.3 link	c.*58G>A		downstream_gene_variant		3		ENSP00000360294.3	F5H1F6

Frequencies

GnomAD3 genomes

AF:

0.000518

AC:

AN:

142964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000204

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000865

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000950

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000835

AC:

192

AN:

229952

Hom.:

AF XY:

0.000835

AC XY:

106

AN XY:

126934

show subpopulations

Gnomad AFR exome

AF:

0.000145

Gnomad AMR exome

AF:

0.000149

Gnomad ASJ exome

AF:

0.000106

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000333

Gnomad FIN exome

AF:

0.00108

Gnomad NFE exome

AF:

0.00149

Gnomad OTH exome

AF:

0.000527

GnomAD4 exome

AF:

0.000864

AC:

1252

AN:

1448944

Hom.:

Cov.:

AF XY:

0.000843

AC XY:

607

AN XY:

720164

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.000136

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.000256

Gnomad4 FIN exome

AF:

0.00108

Gnomad4 NFE exome

AF:

0.00103

Gnomad4 OTH exome

AF:

0.000485

GnomAD4 genome

AF:

0.000517

AC:

AN:

143054

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

69130

show subpopulations

Gnomad4 AFR

AF:

0.0000530

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000205

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000865

Gnomad4 NFE

AF:

0.000950

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000615

Hom.:

Bravo

AF:

0.000540

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000966

AC:

ExAC

AF:

0.000891

AC:

107

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.617G>A (p.R206H) alteration is located in exon 4 (coding exon 4) of the VPS37B gene. This alteration results from a G to A substitution at nucleotide position 617, causing the arginine (R) at amino acid position 206 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

0.26

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.036

T;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.031

MetaRNN

Benign

0.035

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.20

Sift

Benign

0.030

D;D

Sift4G

Benign

0.11

T;.

Polyphen

1.0

D;.

Vest4

0.36

MVP

0.29

MPC

0.99

ClinPred

0.089

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.41

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