dbSNP rs370705512: VPS37D:p.Ala63Gly (chr7-73669468-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001077621.2(VPS37D):c.188C>G(p.Ala63Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000007 in 1,428,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. A63V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

VPS37D
NM_001077621.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.777

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19789976).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077621.2. 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
	VPS37D	NM_001077621.2	MANE Select	c.188C>G	p.Ala63Gly	missense	Exon 2 of 4	NP_001071089.1	Q86XT2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS37D	ENST00000324941.5	TSL:1 MANE Select	c.188C>G	p.Ala63Gly	missense	Exon 2 of 4	ENSP00000320416.4	Q86XT2
VPS37D	ENST00000965880.1		c.188C>G	p.Ala63Gly	missense	Exon 2 of 4	ENSP00000635939.1
VPS37D	ENST00000903466.1		c.188C>G	p.Ala63Gly	missense	Exon 2 of 4	ENSP00000573525.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000700

AC:

AN:

1428238

Hom.:

Cov.:

AF XY:

0.00000848

AC XY:

AN XY:

707640

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32734

American (AMR)

AF:

0.00

AC:

AN:

39936

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25496

East Asian (EAS)

AF:

0.00

AC:

AN:

37786

South Asian (SAS)

AF:

0.00

AC:

AN:

81772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5062

European-Non Finnish (NFE)

AF:

0.00000912

AC:

AN:

1095904

Other (OTH)

AF:

0.00

AC:

AN:

58992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.079

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.0

PhyloP100

0.78

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.4

REVEL

Benign

0.21

Sift

Uncertain

0.010

Sift4G

Uncertain

0.049

Polyphen

0.92

Vest4

0.28

MutPred

0.49

Loss of stability (P = 0.1061)

MVP

0.11

MPC

0.45

ClinPred

0.37

GERP RS

3.4

Varity_R

0.14

gMVP

0.15

Mutation Taster

=88/12

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