rs201895384

chr1-2306226-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_003036.4(SKI):c.1974C>T(p.Arg658=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00673 in 1,560,498 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (46 hom.)
• Consequence: SKI NM_003036.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.173

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 1-2306226-C-T is Benign according to our data. Variant chr1-2306226-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 139117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2306226-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.173 with no splicing effect.
• BS2: High AC in GnomAd at 905 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKI	NM_003036.4	c.1974C>T	p.Arg658=	synonymous_variant	6/7	ENST00000378536.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKI	ENST00000378536.5	c.1974C>T	p.Arg658=	synonymous_variant	6/7	1	NM_003036.4	P1

Frequencies

GnomAD3 genomes AF: 0.00595 AC: 905 AN: 152146 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00795

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00644 AC: 1021 AN: 158584 Hom.: 8 AF XY: 0.00632 AC XY: 545 AN XY: 86176

Gnomad AFR exome AF: 0.000916

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.00250

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00103

Gnomad FIN exome AF: 0.0201

Gnomad NFE exome AF: 0.00923

Gnomad OTH exome AF: 0.00702

GnomAD4 exome AF: 0.00681 AC: 9593 AN: 1408230 Hom.: 46 Cov.: 32 AF XY: 0.00659 AC XY: 4586 AN XY: 695458

Gnomad4 AFR exome AF: 0.000904

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.0000273

Gnomad4 SAS exome AF: 0.000973

Gnomad4 FIN exome AF: 0.0210

Gnomad4 NFE exome AF: 0.00737

Gnomad4 OTH exome AF: 0.00573

GnomAD4 genome AF: 0.00594 AC: 904 AN: 152268 Hom.: 5 Cov.: 33 AF XY: 0.00638 AC XY: 475 AN XY: 74452

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.0218

Gnomad4 NFE AF: 0.00794

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00730 Hom.: 3

Bravo AF: 0.00438

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 07, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2023	- -

Shprintzen-Goldberg syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

SKI: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	8.4
Dann	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs201895384; hg19: chr1-2237665;