rs3772173

chr3-170360444-C-Achr3-170360444-C-Gchr3-170360444-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005414.5(SKIL):c.113C>A(p.Ala38Glu) 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 benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A38V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SKIL NM_005414.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.50

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19628936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKIL	NM_005414.5	c.113C>A	p.Ala38Glu	missense_variant	2/7	ENST00000259119.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKIL	ENST00000259119.9	c.113C>A	p.Ala38Glu	missense_variant	2/7	1	NM_005414.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 58

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	19
Dann	Benign	0.97
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	T;.;T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	0.45	P;P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Benign	0.070
Sift	Benign	0.043	D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D
Polyphen		0.72, 0.66	.;P;.;P;P
Vest4		0.18, 0.21, 0.25, 0.19
MutPred		0.24		Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);.;Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);
MVP		0.84
MPC		0.25
ClinPred		0.49	T
GERP RS		4.4
Varity_R		0.16
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs3772173; hg19: chr3-170078232;