chr3-170360372-C-T

Variant names:

• chr3-170360372-C-T
• NM_005414.5:c.41C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005414.5(SKIL):​c.41C>T​(p.Ser14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000416 in 1,443,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: SKIL NM_005414.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.55
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15635473).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKIL	NM_005414.5	MANE Select	c.41C>T	p.Ser14Leu	missense	Exon 2 of 7	NP_005405.2	P12757-1
	SKIL	NM_001248008.1		c.41C>T	p.Ser14Leu	missense	Exon 1 of 6	NP_001234937.1	P12757-1
	SKIL	NM_001145097.2		c.41C>T	p.Ser14Leu	missense	Exon 1 of 6	NP_001138569.1	P12757-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKIL	ENST00000259119.9	TSL:1 MANE Select	c.41C>T	p.Ser14Leu	missense	Exon 2 of 7	ENSP00000259119.4	P12757-1
	SKIL	ENST00000458537.7	TSL:1	c.41C>T	p.Ser14Leu	missense	Exon 1 of 6	ENSP00000415243.3	P12757-1
	SKIL	ENST00000465590.2	TSL:1	c.41C>T	p.Ser14Leu	missense	Exon 2 of 7	ENSP00000516712.1	P12757-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000416 AC: 6 AN: 1443048 Hom.: 0 Cov.: 29 AF XY: 0.00000279 AC XY: 2 AN XY: 716910

African (AFR) AF: 0.00 AC: 0 AN: 32874

American (AMR) AF: 0.00 AC: 0 AN: 41954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24552

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 82870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.00000544 AC: 6 AN: 1103392

Other (OTH) AF: 0.00 AC: 0 AN: 59560

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.056
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.042
Sift	Benign	0.049	D
Sift4G	Uncertain	0.043	D
Polyphen		0.0020	B
Vest4		0.20
MutPred		0.28		Gain of helix (P = 0.0034)
MVP		0.64
MPC		0.16
ClinPred		0.51	D
GERP RS		4.7
Varity_R		0.11
gMVP		0.13
Mutation Taster		=87/13	polymorphism

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

hg19: chr3-170078160; COSMIC: COSV99378558; COSMIC: COSV99378558;