Variant chr3-170360454-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005414.5(SKIL):c.123A>C(p.Lys41Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SKIL
NM_005414.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.403

Variant links:

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]

SKIL links:

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ACMG classification

Classification made for transcript

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=0.14315423).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKIL	NM_005414.5 linkuse as main transcript	c.123A>C	p.Lys41Asn	missense_variant	2/7	ENST00000259119.9	NP_005405.2	P12757-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKIL	ENST00000259119.9 linkuse as main transcript	c.123A>C	p.Lys41Asn	missense_variant	2/7	1	NM_005414.5	ENSP00000259119.4		P12757-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461662

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 2024

The c.123A>C (p.K41N) alteration is located in exon 2 (coding exon 1) of the SKIL gene. This alteration results from a A to C substitution at nucleotide position 123, causing the lysine (K) at amino acid position 41 to be replaced by an asparagine (N). 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

0.18

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

.;T;.;.;T

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.47

T;.;T;T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.14

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.55

.;N;.;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.4

N;N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.065

T;T;T;T;T

Sift4G

Benign

0.063

T;D;D;D;D

Polyphen

0.70, 0.76

.;P;.;P;P

Vest4

0.061, 0.11, 0.088, 0.056

MutPred

0.23

Loss of methylation at K41 (P = 0.0127);Loss of methylation at K41 (P = 0.0127);.;Loss of methylation at K41 (P = 0.0127);Loss of methylation at K41 (P = 0.0127);

MVP

0.68

MPC

0.31

ClinPred

0.45

GERP RS

4.5

Varity_R

0.077

gMVP

0.13

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over