3-170360401-G-C

Position:

• chr3-170360401-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005414.5(SKIL):​c.70G>C​(p.Asp24His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SKIL NM_005414.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30713105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKIL	NM_005414.5	c.70G>C	p.Asp24His	missense_variant	2/7	ENST00000259119.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKIL	ENST00000259119.9	c.70G>C	p.Asp24His	missense_variant	2/7	1	NM_005414.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

May 08, 2023

The c.70G>C (p.D24H) 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 70, causing the aspartic acid (D) at amino acid position 24 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	Benign	0.19
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;T;.;.;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T;.;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.69	.;N;.;N;N
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.3	N;N;N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		0.98, 0.99	.;D;.;D;D
Vest4		0.30, 0.49, 0.33, 0.30
MutPred		0.18		Gain of glycosylation at S26 (P = 0.0155);Gain of glycosylation at S26 (P = 0.0155);.;Gain of glycosylation at S26 (P = 0.0155);Gain of glycosylation at S26 (P = 0.0155);
MVP		0.84
MPC		0.67
ClinPred		0.94	D
GERP RS		5.7
Varity_R		0.33
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs1736164190; hg19: chr3-170078189;