Variant 8-17247266-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152415.3(VPS37A):c.22A>C(p.Thr8Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T8T) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VPS37A
NM_152415.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.147

Variant links:

Genes affected

VPS37A (HGNC:24928): (VPS37A subunit of ESCRT-I) This gene belongs to the VPS37 family, and encodes a component of the ESCRT-I (endosomal sorting complex required for transport I) protein complex, required for the sorting of ubiquitinated transmembrane proteins into internal vesicles of multivesicular bodies. Expression of this gene is downregulated in hepatocellular carcinoma, and mutations in this gene are associated with autosomal recessive spastic paraplegia-53. A related pseudogene has been identified on chromosome 5. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2012]

VPS37A links:

VPS37A (HGNC:):

VPS37A links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04758215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS37A	NM_152415.3 linkuse as main transcript	c.22A>C	p.Thr8Pro	missense_variant	1/12	ENST00000324849.9	NP_689628.2	Q8NEZ2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS37A	ENST00000324849.9 linkuse as main transcript	c.22A>C	p.Thr8Pro	missense_variant	1/12	1	NM_152415.3	ENSP00000318629.4		Q8NEZ2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1418558

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701712

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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

Cov.:

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

Aug 25, 2024

The c.22A>C (p.T8P) alteration is located in exon 1 (coding exon 1) of the VPS37A gene. This alteration results from a A to C substitution at nucleotide position 22, causing the threonine (T) at amino acid position 8 to be replaced by a proline (P). 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

0.078

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.031

T;T;.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.71

T;T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.048

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;.;L;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.0

N;N;N;D

REVEL

Benign

0.029

Sift

Benign

0.076

T;D;T;D

Sift4G

Benign

0.062

T;T;D;D

Polyphen

0.090

B;.;B;.

Vest4

0.12

MutPred

0.14

Gain of glycosylation at T8 (P = 0.0205);Gain of glycosylation at T8 (P = 0.0205);Gain of glycosylation at T8 (P = 0.0205);Gain of glycosylation at T8 (P = 0.0205);

MVP

0.068

MPC

0.019

ClinPred

0.18

GERP RS

1.5

Varity_R

0.21

gMVP

0.31

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over