Genetic Variant VPS37D:p.Glu12Gln (chr7-73667992-G-C) – 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.34G>C(p.Glu12Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000673 in 148,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. E12K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VPS37D
NM_001077621.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.04

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=0.108348876).

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.34G>C	p.Glu12Gln	missense	Exon 1 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.34G>C	p.Glu12Gln	missense	Exon 1 of 4	ENSP00000320416.4	Q86XT2
VPS37D	ENST00000965880.1		c.34G>C	p.Glu12Gln	missense	Exon 1 of 4	ENSP00000635939.1
VPS37D	ENST00000903466.1		c.34G>C	p.Glu12Gln	missense	Exon 1 of 4	ENSP00000573525.1

Frequencies

GnomAD3 genomes

AF:

0.00000673

AC:

AN:

148620

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:

0.000195

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

953720

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

451030

African (AFR)

AF:

0.00

AC:

AN:

18094

American (AMR)

AF:

0.00

AC:

AN:

4064

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8310

East Asian (EAS)

AF:

0.00

AC:

AN:

11674

South Asian (SAS)

AF:

0.00

AC:

AN:

20024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2480

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

835712

Other (OTH)

AF:

0.00

AC:

AN:

33804

GnomAD4 genome

AF:

0.00000673

AC:

AN:

148620

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72416

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41018

American (AMR)

AF:

0.00

AC:

AN:

14988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3422

East Asian (EAS)

AF:

0.000195

AC:

AN:

5128

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66638

Other (OTH)

AF:

0.00

AC:

AN:

2044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.014

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.34

PhyloP100

2.0

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.060

REVEL

Benign

0.080

Sift

Uncertain

0.0090

Sift4G

Benign

0.24

Polyphen

0.66

Vest4

0.23

MutPred

0.15

Gain of MoRF binding (P = 0.0217)

MVP

0.043

MPC

1.9

ClinPred

0.55

GERP RS

1.7

PromoterAI

0.030

Neutral

(source)

Varity_R

0.15

gMVP

0.24

Mutation Taster

=90/10

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