1-2229222-C-T

Position:

• chr1-2229222-C-T

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.456C>T​(p.Arg152Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,608,254 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R152R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0095 (14 hom., cov: 32)
  • Exomes 𝑓: 0.013 (115 hom.)
• Consequence: SKI NM_003036.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.866

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]

SKI (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-2229222-C-T is Benign according to our data. Variant chr1-2229222-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 139111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2229222-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.866 with no splicing effect.
• BS2: High AC in GnomAd4 at 1446 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKI	NM_003036.4	c.456C>T	p.Arg152Arg	synonymous_variant	1/7	ENST00000378536.5	NP_003027.1
SKI	XM_005244775.4	c.456C>T	p.Arg152Arg	synonymous_variant	1/7		XP_005244832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKI	ENST00000378536.5	c.456C>T	p.Arg152Arg	synonymous_variant	1/7	1	NM_003036.4	ENSP00000367797.4
SKI	ENST00000704337.1	n.137+1698C>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00950 AC: 1446 AN: 152242 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00878 AC: 2060 AN: 234598 Hom.: 13 AF XY: 0.00872 AC XY: 1118 AN XY: 128204

Gnomad AFR exome AF: 0.00254

Gnomad AMR exome AF: 0.00475

Gnomad ASJ exome AF: 0.0199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00254

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0131 AC: 19135 AN: 1455894 Hom.: 115 Cov.: 33 AF XY: 0.0126 AC XY: 9119 AN XY: 723874

Gnomad4 AFR exome AF: 0.00243

Gnomad4 AMR exome AF: 0.00483

Gnomad4 ASJ exome AF: 0.0201

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00264

Gnomad4 FIN exome AF: 0.0125

Gnomad4 NFE exome AF: 0.0151

Gnomad4 OTH exome AF: 0.0115

GnomAD4 genome AF: 0.00949 AC: 1446 AN: 152360 Hom.: 14 Cov.: 32 AF XY: 0.00935 AC XY: 697 AN XY: 74508

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.00842

Gnomad4 ASJ AF: 0.0230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0116

Gnomad4 NFE AF: 0.0139

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0134 Hom.: 6

Bravo AF: 0.00897

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 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. -

Shprintzen-Goldberg syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SKI: BP4, BS1, BS2 -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.92

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: rs149898447; hg19: chr1-2160661;