Variant 7-73671192-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001077621.2(VPS37D):c.572A>T(p.Lys191Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000501 in 1,597,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

VPS37D
NM_001077621.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.833

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08238587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VPS37D	NM_001077621.2 linkuse as main transcript	c.572A>T	p.Lys191Ile	missense_variant	4/4	ENST00000324941.5	NP_001071089.1
VPS37D	XM_017011779.2 linkuse as main transcript	c.449A>T	p.Lys150Ile	missense_variant	4/4		XP_016867268.1
VPS37D	XM_047419927.1 linkuse as main transcript	c.344A>T	p.Lys115Ile	missense_variant	4/4		XP_047275883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS37D	ENST00000324941.5 linkuse as main transcript	c.572A>T	p.Lys191Ile	missense_variant	4/4	1	NM_001077621.2	ENSP00000320416	P1
VPS37D	ENST00000451519.1 linkuse as main transcript	c.317A>T	p.Lys106Ile	missense_variant	2/2	5		ENSP00000413337

Frequencies

GnomAD3 genomes

AF:

0.0000331

AC:

AN:

150960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000181

AC:

AN:

221436

Hom.:

AF XY:

0.00

AC XY:

AN XY:

122468

show subpopulations

Gnomad AFR exome

AF:

0.000159

Gnomad AMR exome

AF:

0.0000602

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1446498

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718578

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.0000455

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000331

AC:

AN:

150960

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73714

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

ExAC

AF:

0.0000171

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.572A>T (p.K191I) alteration is located in exon 4 (coding exon 4) of the VPS37D gene. This alteration results from a A to T substitution at nucleotide position 572, causing the lysine (K) at amino acid position 191 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.038

T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.082

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.

MutationTaster

Benign

0.88

N;N

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.10

Sift

Benign

0.067

T;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.99

D;.

Vest4

0.28

MutPred

0.25

Loss of methylation at K191 (P = 0.0032);.;

MVP

0.16

MPC

0.85

ClinPred

0.16

GERP RS

1.5

Varity_R

0.13

gMVP

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over