Genetic Variant VPS37D:p.Glu12Lys (chr7-73667992-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001077621.2(VPS37D):c.34G>A(p.Glu12Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000998 in 1,102,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000067 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000010 ( 0 hom. )

Consequence

VPS37D
NM_001077621.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1131216).

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>A	p.Glu12Lys	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>A	p.Glu12Lys	missense	Exon 1 of 4	ENSP00000320416.4	Q86XT2
VPS37D	ENST00000965880.1		c.34G>A	p.Glu12Lys	missense	Exon 1 of 4	ENSP00000635939.1
VPS37D	ENST00000903466.1		c.34G>A	p.Glu12Lys	missense	Exon 1 of 4	ENSP00000573525.1

Frequencies

GnomAD3 genomes

AF:

0.0000673

AC:

AN:

148620

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000667

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

AF:

0.00000105

AC:

AN:

953720

Hom.:

Cov.:

AF XY:

0.00000222

AC XY:

AN XY:

451030

show subpopulations

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:

0.00000120

AC:

AN:

835712

Other (OTH)

AF:

0.00

AC:

AN:

33804

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000673

AC:

AN:

148620

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

72416

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41018

American (AMR)

AF:

0.000667

AC:

AN:

14988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3422

East Asian (EAS)

AF:

0.00

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: 0.555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000756

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

Pathogenic

0.63

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.014

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.67

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.34

PhyloP100

2.0

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.46

REVEL

Benign

0.066

Sift

Uncertain

0.0080

Sift4G

Benign

0.25

Polyphen

0.46

Vest4

0.29

MutPred

0.28

Gain of MoRF binding (P = 0.0017)

MVP

0.043

MPC

2.1

ClinPred

0.75

GERP RS

1.7

PromoterAI

0.028

Neutral

(source)

Varity_R

0.20

gMVP

0.25

Mutation Taster

=87/13

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over