rs730880212

chr1-2304386-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003036.4(SKI):c.1568C>T(p.Ser523Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000683 in 1,551,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S523A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -0.0770

Genes affected

SKI (HGNC:10896): (SKI proto-oncogene) This gene encodes the nuclear protooncogene protein homolog of avian sarcoma viral (v-ski) oncogene. It functions as a repressor of TGF-beta signaling, and may play a role in neural tube development and muscle differentiation. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013550699).
• BP6: Variant 1-2304386-C-T is Benign according to our data. Variant chr1-2304386-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 180522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKI	NM_003036.4	c.1568C>T	p.Ser523Leu	missense_variant	5/7	ENST00000378536.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKI	ENST00000378536.5	c.1568C>T	p.Ser523Leu	missense_variant	5/7	1	NM_003036.4	P1
SKI	ENST00000507179.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000179 AC: 28 AN: 156742 Hom.: 0 AF XY: 0.000169 AC XY: 14 AN XY: 82736

Gnomad AFR exome AF: 0.000113

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00176

Gnomad EAS exome AF: 0.0000873

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.0000672 AC: 94 AN: 1399696 Hom.: 0 Cov.: 34 AF XY: 0.0000767 AC XY: 53 AN XY: 690558

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.000139

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000269

Gnomad4 OTH exome AF: 0.000121

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74376

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000215 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.0000763 AC: 8

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arterial dissection Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Oct 06, 2014

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 18, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Shprintzen-Goldberg syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

SKI-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	12
Dann	Benign	0.94
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.20
Sift	Benign	0.43	T
Sift4G	Benign	0.36	T
Polyphen		0.0010	B
Vest4		0.10
MVP		0.45
MPC		0.18
ClinPred		0.015	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.039
gMVP		0.080

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs730880212; hg19: chr1-2235825;