chr3-170360934-G-C

Position:

• chr3-170360934-G-C

Variant summary

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

The NM_005414.5(SKIL):​c.603G>C​(p.Gln201His) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SKIL NM_005414.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83

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 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, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKIL	NM_005414.5	c.603G>C	p.Gln201His	missense_variant	2/7	ENST00000259119.9	NP_005405.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKIL	ENST00000259119.9	c.603G>C	p.Gln201His	missense_variant	2/7	1	NM_005414.5	ENSP00000259119.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

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

Dec 02, 2024

The c.603G>C (p.Q201H) alteration is located in exon 2 (coding exon 1) of the SKIL gene. This alteration results from a G to C substitution at nucleotide position 603, causing the glutamine (Q) at amino acid position 201 to be replaced by a histidine (H). 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	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	.;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.0	M;.;M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.9	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.92
MutPred		0.91		Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.98
MPC		0.71
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.87
gMVP		0.96

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: chr3-170078722;