17-64555928-T-A

Position:

• chr17-64555928-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_022739.4(SMURF2):​c.1502A>T​(p.Asp501Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMURF2 NM_022739.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMURF2	NM_022739.4	c.1502A>T	p.Asp501Val	missense_variant	14/19	ENST00000262435.14	NP_073576.1
SMURF2	XM_047436546.1	c.1508A>T	p.Asp503Val	missense_variant	14/19		XP_047292502.1
SMURF2	XM_005257585.4	c.1463A>T	p.Asp488Val	missense_variant	13/18		XP_005257642.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMURF2	ENST00000262435.14	c.1502A>T	p.Asp501Val	missense_variant	14/19	1	NM_022739.4	ENSP00000262435	P1
SMURF2	ENST00000578386.5	c.*1324A>T		3_prime_UTR_variant, NMD_transcript_variant	14/19	1		ENSP00000464432
SMURF2	ENST00000585301.1	c.1463A>T	p.Asp488Val	missense_variant	13/14	5		ENSP00000463804
SMURF2	ENST00000582081.5	c.*1409A>T		3_prime_UTR_variant, NMD_transcript_variant	14/19	5		ENSP00000463531

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2024

The c.1502A>T (p.D501V) alteration is located in exon 14 (coding exon 14) of the SMURF2 gene. This alteration results from a A to T substitution at nucleotide position 1502, causing the aspartic acid (D) at amino acid position 501 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	27
DANN	Benign	0.95
DEOGEN2	Benign	0.41	T;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.057	D
MutationAssessor	Pathogenic	3.8	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.7	D;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.96	D;.
Vest4		0.94
MutPred		0.87		Gain of sheet (P = 0.1208);.;
MVP		0.92
MPC		2.0
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.92
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-62552046;