chr17-64561602-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_022739.4(SMURF2):ā€‹c.1214A>Gā€‹(p.Glu405Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,607,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000099 ( 0 hom., cov: 31)
Exomes š‘“: 0.00010 ( 0 hom. )

Consequence

SMURF2
NM_022739.4 missense, splice_region

Scores

8
10
1
Splicing: ADA: 0.03638
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.80
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.881
BS2
High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMURF2NM_022739.4 linkuse as main transcriptc.1214A>G p.Glu405Gly missense_variant, splice_region_variant 12/19 ENST00000262435.14 NP_073576.1
SMURF2XM_047436546.1 linkuse as main transcriptc.1220A>G p.Glu407Gly missense_variant, splice_region_variant 12/19 XP_047292502.1
SMURF2XM_005257585.4 linkuse as main transcriptc.1175A>G p.Glu392Gly missense_variant, splice_region_variant 11/18 XP_005257642.1
SMURF2XR_007065425.1 linkuse as main transcriptn.4272A>G splice_region_variant, non_coding_transcript_exon_variant 12/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMURF2ENST00000262435.14 linkuse as main transcriptc.1214A>G p.Glu405Gly missense_variant, splice_region_variant 12/191 NM_022739.4 ENSP00000262435 P1

Frequencies

GnomAD3 genomes
AF:
0.0000986
AC:
15
AN:
152116
Hom.:
0
Cov.:
31
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000221
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000201
AC:
5
AN:
248522
Hom.:
0
AF XY:
0.0000149
AC XY:
2
AN XY:
134598
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000442
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000103
AC:
150
AN:
1455656
Hom.:
0
Cov.:
28
AF XY:
0.0000939
AC XY:
68
AN XY:
724522
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
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:
0.000125
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.0000986
AC:
15
AN:
152116
Hom.:
0
Cov.:
31
AF XY:
0.000121
AC XY:
9
AN XY:
74308
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000221
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000217
Hom.:
0
Bravo
AF:
0.0000831
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

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 GeneticsMar 28, 2024The c.1214A>G (p.E405G) alteration is located in exon 12 (coding exon 12) of the SMURF2 gene. This alteration results from a A to G substitution at nucleotide position 1214, causing the glutamic acid (E) at amino acid position 405 to be replaced by a glycine (G). 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
0.78
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
27
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.71
D;T
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.88
D;D
MetaSVM
Uncertain
0.25
D
MutationAssessor
Uncertain
2.1
M;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-5.8
D;.
REVEL
Pathogenic
0.85
Sift
Uncertain
0.028
D;.
Sift4G
Uncertain
0.0020
D;.
Polyphen
1.0
D;.
Vest4
0.83
MVP
0.86
MPC
1.8
ClinPred
0.83
D
GERP RS
4.8
Varity_R
0.55
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.036
dbscSNV1_RF
Benign
0.16
SpliceAI score (max)
0.020
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: rs782498467; hg19: chr17-62557720; API