chr3-170361273-A-T

Variant names:

• chr3-170361273-A-T
• rs193920870
• NM_005414.5:c.942A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005414.5(SKIL):​c.942A>T​(p.Arg314Ser) variant causes a missense change involving the alteration of a non-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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SKIL NM_005414.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.70
• Publications: 2 publications found

Genes affected

SKIL (HGNC:10897): (SKI like proto-oncogene) The protein encoded by this gene is a component of the SMAD pathway, which regulates cell growth and differentiation through transforming growth factor-beta (TGFB). In the absence of ligand, the encoded protein binds to the promoter region of TGFB-responsive genes and recruits a nuclear repressor complex. TGFB signaling causes SMAD3 to enter the nucleus and degrade this protein, allowing these genes to be activated. Four transcript variants encoding three different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005414.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKIL	NM_005414.5	MANE Select	c.942A>T	p.Arg314Ser	missense	Exon 2 of 7	NP_005405.2
	SKIL	NM_001248008.1		c.942A>T	p.Arg314Ser	missense	Exon 1 of 6	NP_001234937.1
	SKIL	NM_001145098.3		c.882A>T	p.Arg294Ser	missense	Exon 3 of 8	NP_001138570.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKIL	ENST00000259119.9	TSL:1 MANE Select	c.942A>T	p.Arg314Ser	missense	Exon 2 of 7	ENSP00000259119.4
	SKIL	ENST00000458537.7	TSL:1	c.942A>T	p.Arg314Ser	missense	Exon 1 of 6	ENSP00000415243.3
	SKIL	ENST00000465590.2	TSL:1	c.942A>T	p.Arg314Ser	missense	Exon 2 of 7	ENSP00000516712.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Prostate cancer Uncertain:1

Science for Life laboratory, Karolinska Institutet

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.084	T
Polyphen		1.0	D
Vest4		0.86
MutPred		0.70		Gain of ubiquitination at K313 (P = 0.0526)
MVP		0.95
MPC		0.65
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.95
gMVP		0.81
Mutation Taster		=19/81	disease causing

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

Other links and lift over

dbSNP: rs193920870; hg19: chr3-170079061; COSMIC: COSV52059034; COSMIC: COSV52059034;