3-170360444-C-T

Variant names:

• chr3-170360444-C-T
• rs3772173
• NM_005414.5:c.113C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005414.5(SKIL):​c.113C>T​(p.Ala38Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.793 in 1,613,278 control chromosomes in the GnomAD database, including 511,721 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.73 (41424 hom., cov: 32)
  • Exomes 𝑓: 0.80 (470297 hom.)
• Consequence: SKIL NM_005414.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.50
• Publications: 38 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.5070674E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

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.113C>T	p.Ala38Val	missense	Exon 2 of 7	NP_005405.2	P12757-1
	SKIL	NM_001248008.1		c.113C>T	p.Ala38Val	missense	Exon 1 of 6	NP_001234937.1	P12757-1
	SKIL	NM_001145098.3		c.53C>T	p.Ala18Val	missense	Exon 3 of 8	NP_001138570.1	P12757-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKIL	ENST00000259119.9	TSL:1 MANE Select	c.113C>T	p.Ala38Val	missense	Exon 2 of 7	ENSP00000259119.4	P12757-1
	SKIL	ENST00000458537.7	TSL:1	c.113C>T	p.Ala38Val	missense	Exon 1 of 6	ENSP00000415243.3	P12757-1
	SKIL	ENST00000465590.2	TSL:1	c.113C>T	p.Ala38Val	missense	Exon 2 of 7	ENSP00000516712.1	P12757-1

Frequencies

GnomAD3 genomes AF: 0.726 AC: 110264 AN: 151924 Hom.: 41424 Cov.: 32

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.764

Gnomad AMR AF: 0.784

Gnomad ASJ AF: 0.823

Gnomad EAS AF: 0.844

Gnomad SAS AF: 0.706

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.811

Gnomad OTH AF: 0.736

GnomAD2 exomes AF: 0.788 AC: 197637 AN: 250924 AF XY: 0.791

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.807

Gnomad ASJ exome AF: 0.831

Gnomad EAS exome AF: 0.838

Gnomad FIN exome AF: 0.868

Gnomad NFE exome AF: 0.815

Gnomad OTH exome AF: 0.802

GnomAD4 exome AF: 0.800 AC: 1169142 AN: 1461236 Hom.: 470297 Cov.: 58 AF XY: 0.798 AC XY: 580369 AN XY: 726910

African (AFR) AF: 0.495 AC: 16561 AN: 33442

American (AMR) AF: 0.804 AC: 35890 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.832 AC: 21731 AN: 26104

East Asian (EAS) AF: 0.860 AC: 34124 AN: 39698

South Asian (SAS) AF: 0.717 AC: 61789 AN: 86170

European-Finnish (FIN) AF: 0.872 AC: 46545 AN: 53394

Middle Eastern (MID) AF: 0.760 AC: 4381 AN: 5766

European-Non Finnish (NFE) AF: 0.810 AC: 900897 AN: 1111650

Other (OTH) AF: 0.782 AC: 47224 AN: 60370

GnomAD4 genome AF: 0.725 AC: 110278 AN: 152042 Hom.: 41424 Cov.: 32 AF XY: 0.728 AC XY: 54116 AN XY: 74312

African (AFR) AF: 0.505 AC: 20921 AN: 41402

American (AMR) AF: 0.784 AC: 11977 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.823 AC: 2854 AN: 3468

East Asian (EAS) AF: 0.844 AC: 4370 AN: 5178

South Asian (SAS) AF: 0.707 AC: 3401 AN: 4810

European-Finnish (FIN) AF: 0.862 AC: 9120 AN: 10574

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.811 AC: 55174 AN: 68020

Other (OTH) AF: 0.730 AC: 1541 AN: 2112

Alfa AF: 0.787 Hom.: 131785

Bravo AF: 0.713

TwinsUK AF: 0.806 AC: 2987

ALSPAC AF: 0.832 AC: 3207

ESP6500AA AF: 0.524 AC: 2310

ESP6500EA AF: 0.820 AC: 7054

ExAC AF: 0.780 AC: 94711

Asia WGS AF: 0.721 AC: 2506 AN: 3478

EpiCase AF: 0.810

EpiControl AF: 0.809

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.15
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	6.5e-7	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.20	N
PhyloP100		2.5
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.022
MPC		0.18
ClinPred		0.0083	T
GERP RS		4.4
Varity_R		0.047
gMVP		0.14
Mutation Taster		=99/1	polymorphism (auto)

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: rs3772173; hg19: chr3-170078232; COSMIC: COSV52058833; COSMIC: COSV52058833;