Variant 11-61132332-T-G 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_017966.5(VPS37C):c.556A>C(p.Thr186Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,599,194 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

VPS37C
NM_017966.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0570

Variant links:

Genes affected

VPS37C (HGNC:26097): (VPS37C subunit of ESCRT-I) VPS37C is a subunit of ESCRT-I (endosomal sorting complex required for transport I), a complex in the class E vacuolar protein sorting (VPS) pathway required for sorting ubiquitinated transmembrane proteins into internal vesicles of multivesicular bodies (Eastman et al., 2005 [PubMed 15509564]).[supplied by OMIM, Mar 2008]

VPS37C links:

Genome browser will be placed here

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=0.057298303).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS37C	NM_017966.5 linkuse as main transcript	c.556A>C	p.Thr186Pro	missense_variant	5/5	ENST00000301765.10	NP_060436.4	A5D8V6
VPS37C	XM_005274077.4 linkuse as main transcript	c.556A>C	p.Thr186Pro	missense_variant	5/5		XP_005274134.1	A5D8V6
VPS37C	XM_047427178.1 linkuse as main transcript	c.*197A>C		3_prime_UTR_variant	5/5		XP_047283134.1
VPS37C	XM_047427179.1 linkuse as main transcript	c.*197A>C		3_prime_UTR_variant	5/5		XP_047283135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS37C	ENST00000301765.10 linkuse as main transcript	c.556A>C	p.Thr186Pro	missense_variant	5/5	1	NM_017966.5	ENSP00000301765.5		A5D8V6

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151832

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000159

AC:

AN:

1447362

Hom.:

Cov.:

AF XY:

0.0000153

AC XY:

AN XY:

718630

show subpopulations

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:

0.0000208

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151832

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74138

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

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

Dec 10, 2024

The c.556A>C (p.T186P) alteration is located in exon 5 (coding exon 4) of the VPS37C gene. This alteration results from a A to C substitution at nucleotide position 556, causing the threonine (T) at amino acid position 186 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

0.062

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

4.3

DANN

Benign

0.68

DEOGEN2

Benign

0.0077

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.39

M_CAP

Benign

0.012

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PrimateAI

Uncertain

0.66

PROVEAN

Benign

0.30

REVEL

Benign

0.023

Sift

Benign

0.088

Sift4G

Benign

0.36

Polyphen

0.0010

Vest4

0.10

MutPred

0.14

Loss of phosphorylation at T186 (P = 0.0107);

MVP

0.15

MPC

0.20

ClinPred

0.047

GERP RS

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.047

gMVP

0.20

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