Variant chr17-64562965-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_022739.4(SMURF2):c.1018C>T(p.Arg340Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000808 in 1,609,742 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

SMURF2
NM_022739.4 missense, splice_region

Scores

Splicing: ADA: 0.00006992

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.57

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]

SMURF2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SMURF2	NM_022739.4 linkuse as main transcript	c.1018C>T	p.Arg340Trp	missense_variant, splice_region_variant	11/19	ENST00000262435.14	NP_073576.1
SMURF2	XM_047436546.1 linkuse as main transcript	c.1024C>T	p.Arg342Trp	missense_variant, splice_region_variant	11/19		XP_047292502.1
SMURF2	XM_005257585.4 linkuse as main transcript	c.979C>T	p.Arg327Trp	missense_variant, splice_region_variant	10/18		XP_005257642.1
SMURF2	XR_007065425.1 linkuse as main transcript	n.4188C>T		splice_region_variant, non_coding_transcript_exon_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMURF2	ENST00000262435.14 linkuse as main transcript	c.1018C>T	p.Arg340Trp	missense_variant, splice_region_variant	11/19	1	NM_022739.4	ENSP00000262435	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248368

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134268

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000592

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000823

AC:

AN:

1457610

Hom.:

Cov.:

AF XY:

0.00000966

AC XY:

AN XY:

724768

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000453

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000631

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

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 17, 2023

The c.1018C>T (p.R340W) alteration is located in exon 11 (coding exon 11) of the SMURF2 gene. This alteration results from a C to T substitution at nucleotide position 1018, causing the arginine (R) at amino acid position 340 to be replaced by a tryptophan (W). 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

0.29

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Uncertain

0.59

D;T

Eigen

Benign

0.15

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.58

D;D

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.2

L;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.3

D;.

REVEL

Uncertain

0.33

Sift

Benign

0.060

T;.

Sift4G

Uncertain

0.0060

D;.

Polyphen

0.97

D;.

Vest4

0.64

MutPred

0.50

Loss of disorder (P = 8e-04);.;

MVP

0.74

MPC

1.0

ClinPred

0.81

GERP RS

2.6

Varity_R

0.081

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000070

dbscSNV1_RF

Benign

0.0020

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