Genetic Variant NM_024667.3:c.559G>T (chr12-122867415-C-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.559G>T(p.Ala187Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 59,190 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A187T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000017 ( 0 hom., cov: 13)

Consequence

VPS37B
NM_024667.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.284

Publications

2 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:

Genome browser will be placed here

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=0.059434235).

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.559G>T	p.Ala187Ser	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.559G>T	p.Ala187Ser	missense	Exon 4 of 4	ENSP00000267202.2	Q9H9H4
VPS37B	ENST00000535765.5	TSL:3	c.553G>T	p.Ala185Ser	missense	Exon 4 of 4	ENSP00000446075.1	F5H4M0
VPS37B	ENST00000852158.1		c.304G>T	p.Ala102Ser	missense	Exon 2 of 2	ENSP00000522217.1

Frequencies

GnomAD3 genomes

AF:

0.0000169

AC:

AN:

59190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000426

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000424

AC:

AN:

235964

AF XY:

0.00000777

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000169

AC:

AN:

59190

Hom.:

Cov.:

AF XY:

0.0000355

AC XY:

AN XY:

28156

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

13226

American (AMR)

AF:

0.00

AC:

AN:

4316

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1556

East Asian (EAS)

AF:

0.00

AC:

AN:

2928

South Asian (SAS)

AF:

0.000426

AC:

AN:

2350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

116

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

30424

Other (OTH)

AF:

0.00

AC:

AN:

630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

2.8

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.019

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.48

M_CAP

Benign

0.039

MetaRNN

Benign

0.059

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.28

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.54

REVEL

Benign

0.040

Sift

Benign

0.53

Sift4G

Benign

0.47

Polyphen

0.23

Vest4

0.075

MutPred

0.24

Gain of glycosylation at A187 (P = 4e-04)

MVP

0.18

MPC

0.25

ClinPred

0.050

GERP RS

2.2

Varity_R

0.037

gMVP

0.27

Mutation Taster

=92/8

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

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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