12-122867159-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_024667.3(VPS37B):​c.815C>T​(p.Pro272Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,552,614 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 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

VPS37B
NM_024667.3 missense

Scores

1
10
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.63
Variant links:
Genes affected
VPS37B (HGNC:25754): (VPS37B subunit of ESCRT-I) Enables calcium-dependent protein binding activity. Involved in positive regulation of viral budding via host ESCRT complex. Located in endosome membrane; midbody; and plasma membrane. Part of ESCRT I complex. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.27017507).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VPS37BNM_024667.3 linkuse as main transcriptc.815C>T p.Pro272Leu missense_variant 4/4 ENST00000267202.7 NP_078943.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VPS37BENST00000267202.7 linkuse as main transcriptc.815C>T p.Pro272Leu missense_variant 4/41 NM_024667.3 ENSP00000267202 P1
VPS37BENST00000535765.5 linkuse as main transcriptc.809C>T p.Pro270Leu missense_variant 4/43 ENSP00000446075

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
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:
0.0000329
AC:
6
AN:
182334
Hom.:
0
AF XY:
0.0000202
AC XY:
2
AN XY:
98938
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000375
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:
0.0000207
AC:
29
AN:
1400458
Hom.:
0
Cov.:
32
AF XY:
0.0000231
AC XY:
16
AN XY:
692602
show subpopulations
Gnomad4 AFR exome
AF:
0.000416
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000760
Gnomad4 SAS exome
AF:
0.0000133
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000644
Gnomad4 OTH exome
AF:
0.0000865
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152156
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000385
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000416
AC:
5

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 submitterclinical testingAmbry GeneticsJul 25, 2023The c.815C>T (p.P272L) alteration is located in exon 4 (coding exon 4) of the VPS37B gene. This alteration results from a C to T substitution at nucleotide position 815, causing the proline (P) at amino acid position 272 to be replaced by a leucine (L). 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
0.093
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.18
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.19
T;.
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.86
D;T
M_CAP
Benign
0.056
D
MetaRNN
Benign
0.27
T;T
MetaSVM
Benign
-0.42
T
MutationAssessor
Uncertain
2.3
M;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-3.4
D;D
REVEL
Uncertain
0.34
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.0050
D;.
Polyphen
0.95
P;.
Vest4
0.45
MVP
0.17
MPC
0.47
ClinPred
0.46
T
GERP RS
5.2
Varity_R
0.43
gMVP
0.27

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.

Other links and lift over

dbSNP: rs761476904; hg19: chr12-123351706; API