Genetic Variant VPS37B:p.Leu275Phe (chr12-122867151-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024667.3(VPS37B):c.823C>T(p.Leu275Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,392,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VPS37B
NM_024667.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.04

Publications

0 publications found

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:

ENSG00000256152 (HGNC:):

ENSG00000256152 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06773466).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024667.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS37B	NM_024667.3	MANE Select	c.823C>T	p.Leu275Phe	missense	Exon 4 of 4	NP_078943.1	Q9H9H4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS37B	ENST00000267202.7	TSL:1 MANE Select	c.823C>T	p.Leu275Phe	missense	Exon 4 of 4	ENSP00000267202.2	Q9H9H4
VPS37B	ENST00000852158.1		c.568C>T	p.Leu190Phe	missense	Exon 2 of 2	ENSP00000522217.1
VPS37B	ENST00000535765.5	TSL:3	c.*3C>T		downstream_gene	N/A	ENSP00000446075.1	F5H4M0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1392666

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

688178

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30868

American (AMR)

AF:

0.00

AC:

AN:

31490

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20846

East Asian (EAS)

AF:

0.00

AC:

AN:

39416

South Asian (SAS)

AF:

0.00

AC:

AN:

73384

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49026

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5138

European-Non Finnish (NFE)

AF:

0.00000184

AC:

AN:

1085118

Other (OTH)

AF:

0.00

AC:

AN:

57380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.017

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.58

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.67

M_CAP

Benign

0.024

MetaRNN

Benign

0.068

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

1.0

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.42

REVEL

Benign

0.031

Sift

Benign

0.23

Sift4G

Benign

0.71

Polyphen

0.0040

Vest4

0.15

MutPred

0.25

Loss of catalytic residue at L275 (P = 0.0342)

MVP

0.10

MPC

0.29

ClinPred

0.080

GERP RS

2.4

Varity_R

0.044

gMVP

0.098

Mutation Taster

=85/15

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over