rs114345135

Positions:

• chr1-2304074-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003036.4(SKI):​c.1446G>A​(p.Ala482=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00839 in 1,612,576 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (60 hom.)
• Consequence: SKI NM_003036.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.23

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-2304074-G-A is Benign according to our data. Variant chr1-2304074-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 139115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2304074-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.23 with no splicing effect.
• BS2: High AC in GnomAd4 at 847 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKI	NM_003036.4	c.1446G>A	p.Ala482=	synonymous_variant	4/7	ENST00000378536.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKI	ENST00000378536.5	c.1446G>A	p.Ala482=	synonymous_variant	4/7	1	NM_003036.4	P1
SKI	ENST00000507179.1	n.429G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00557 AC: 848 AN: 152214 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00988

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00908

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00568 AC: 1397 AN: 245914 Hom.: 11 AF XY: 0.00546 AC XY: 731 AN XY: 133790

Gnomad AFR exome AF: 0.00145

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.000603

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00190

Gnomad FIN exome AF: 0.00989

Gnomad NFE exome AF: 0.00883

Gnomad OTH exome AF: 0.00530

GnomAD4 exome AF: 0.00868 AC: 12679 AN: 1460244 Hom.: 60 Cov.: 32 AF XY: 0.00851 AC XY: 6180 AN XY: 726416

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.000613

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.00970

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.00805

GnomAD4 genome AF: 0.00556 AC: 847 AN: 152332 Hom.: 4 Cov.: 32 AF XY: 0.00517 AC XY: 385 AN XY: 74486

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00988

Gnomad4 NFE AF: 0.00907

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00772 Hom.: 2

Bravo AF: 0.00504

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00845

EpiControl AF: 0.00824

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Shprintzen-Goldberg syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 13, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2016

This alteration is classified as 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

SKI: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	1.2
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs114345135; hg19: chr1-2235513;