7-73669468-C-T

Variant summary

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

The NM_001077621.2(VPS37D):​c.188C>T​(p.Ala63Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,580,478 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

VPS37D
NM_001077621.2 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.777
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]

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=0.088446796).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VPS37DNM_001077621.2 linkc.188C>T p.Ala63Val missense_variant 2/4 ENST00000324941.5 NP_001071089.1 Q86XT2
VPS37DXM_017011779.2 linkc.65C>T p.Ala22Val missense_variant 2/4 XP_016867268.1
VPS37DXM_047419927.1 linkc.-41C>T 5_prime_UTR_variant 2/4 XP_047275883.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VPS37DENST00000324941.5 linkc.188C>T p.Ala63Val missense_variant 2/41 NM_001077621.2 ENSP00000320416.4 Q86XT2
VPS37DENST00000451519.1 linkc.138+1372C>T intron_variant 5 ENSP00000413337.1 C9JYT9

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152240
Hom.:
0
Cov.:
31
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000576
AC:
11
AN:
191072
Hom.:
0
AF XY:
0.0000578
AC XY:
6
AN XY:
103882
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000346
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000392
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000111
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000255
AC:
364
AN:
1428238
Hom.:
1
Cov.:
31
AF XY:
0.000242
AC XY:
171
AN XY:
707640
show subpopulations
Gnomad4 AFR exome
AF:
0.0000611
Gnomad4 AMR exome
AF:
0.0000250
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000367
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000318
Gnomad4 OTH exome
AF:
0.000153
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152240
Hom.:
0
Cov.:
31
AF XY:
0.0000134
AC XY:
1
AN XY:
74382
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000167
Hom.:
0
Bravo
AF:
0.0000680
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000265
AC:
1
ESP6500EA
AF:
0.000123
AC:
1
ExAC
AF:
0.0000670
AC:
8

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 GeneticsDec 18, 2023The c.188C>T (p.A63V) alteration is located in exon 2 (coding exon 2) of the VPS37D gene. This alteration results from a C to T substitution at nucleotide position 188, causing the alanine (A) at amino acid position 63 to be replaced by a valine (V). 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
0.12
BayesDel_addAF
Benign
-0.081
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Benign
0.26
T
Eigen
Benign
-0.56
Eigen_PC
Benign
-0.48
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.80
T
M_CAP
Benign
0.072
D
MetaRNN
Benign
0.088
T
MetaSVM
Benign
-0.80
T
MutationAssessor
Benign
-0.34
N
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-2.6
D
REVEL
Benign
0.16
Sift
Uncertain
0.0070
D
Sift4G
Uncertain
0.029
D
Polyphen
0.25
B
Vest4
0.31
MVP
0.082
MPC
0.38
ClinPred
0.13
T
GERP RS
3.4
Varity_R
0.15
gMVP
0.29

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: rs370705512; hg19: chr7-73083798; API