Genetic Variant VPS37A:p.Ser289Thr (chr8-17280263-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_152415.3(VPS37A):c.866G>C(p.Ser289Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. S289R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VPS37A
NM_152415.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.52

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 53
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

VPS37A 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=0.18183449).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS37A	NM_152415.3 link	c.866G>C	p.Ser289Thr	missense_variant	Exon 8 of 12	ENST00000324849.9	NP_689628.2	Q8NEZ2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS37A	ENST00000324849.9 link	c.866G>C	p.Ser289Thr	missense_variant	Exon 8 of 12	1	NM_152415.3	ENSP00000318629.4		Q8NEZ2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460594

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726516

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33430

American (AMR)

AF:

0.00

AC:

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39610

South Asian (SAS)

AF:

0.00

AC:

AN:

85992

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111392

Other (OTH)

AF:

0.00

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.056

T;.;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.036

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.2

L;.;.

PhyloP100

2.5

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.50

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.42

T;T;T

Sift4G

Benign

0.58

T;T;T

Polyphen

0.14

B;B;.

Vest4

0.20

MutPred

0.43

Loss of phosphorylation at S289 (P = 0.0598);.;.;

MVP

0.26

MPC

0.014

ClinPred

0.30

GERP RS

3.1

Varity_R

0.060

gMVP

0.16

Mutation Taster

=96/4

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over