17-64557621-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_022739.4(SMURF2):ā€‹c.1418C>Gā€‹(p.Ser473Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,441,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

SMURF2
NM_022739.4 missense

Scores

12
4
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.82
Variant links:
Genes affected
SMURF2 (HGNC:16809): (SMAD specific E3 ubiquitin protein ligase 2) Enables SMAD binding activity; identical protein binding activity; and ubiquitin-protein transferase activity. Involved in negative regulation of transforming growth factor beta receptor signaling pathway; positive regulation of trophoblast cell migration; and ubiquitin-dependent SMAD protein catabolic process. Located in nuclear speck. Part of ubiquitin ligase 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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMURF2NM_022739.4 linkuse as main transcriptc.1418C>G p.Ser473Cys missense_variant 13/19 ENST00000262435.14 NP_073576.1
SMURF2XM_047436546.1 linkuse as main transcriptc.1424C>G p.Ser475Cys missense_variant 13/19 XP_047292502.1
SMURF2XM_005257585.4 linkuse as main transcriptc.1379C>G p.Ser460Cys missense_variant 12/18 XP_005257642.1
SMURF2XR_007065425.1 linkuse as main transcript downstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMURF2ENST00000262435.14 linkuse as main transcriptc.1418C>G p.Ser473Cys missense_variant 13/191 NM_022739.4 ENSP00000262435 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.94e-7
AC:
1
AN:
1441756
Hom.:
0
Cov.:
27
AF XY:
0.00
AC XY:
0
AN XY:
718452
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:
9.13e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

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 GeneticsApr 10, 2023The c.1418C>G (p.S473C) alteration is located in exon 13 (coding exon 13) of the SMURF2 gene. This alteration results from a C to G substitution at nucleotide position 1418, causing the serine (S) at amino acid position 473 to be replaced by a cysteine (C). 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
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.060
CADD
Pathogenic
28
DANN
Benign
0.88
DEOGEN2
Uncertain
0.42
T;T
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Benign
0.060
D
MetaRNN
Pathogenic
0.82
D;D
MetaSVM
Uncertain
0.034
D
MutationAssessor
Pathogenic
3.2
M;.
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-4.5
D;.
REVEL
Uncertain
0.44
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0010
D;.
Polyphen
1.0
D;.
Vest4
0.72
MutPred
0.68
Loss of disorder (P = 8e-04);.;
MVP
0.69
MPC
1.7
ClinPred
0.93
D
GERP RS
5.8
Varity_R
0.76
gMVP
0.94

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: rs1969141734; hg19: chr17-62553739; API