rs115746142

Positions:

• chr1-2229060-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003036.4(SKI):​c.294C>T​(p.Thr98=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,606,478 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T98T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (25 hom.)
• Consequence: SKI NM_003036.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.835

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-2229060-C-T is Benign according to our data. Variant chr1-2229060-C-T is described in ClinVar as [Benign]. Clinvar id is 213681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2229060-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.835 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0112 (1704/152218) while in subpopulation AFR AF= 0.0375 (1557/41542). AF 95% confidence interval is 0.0359. There are 33 homozygotes in gnomad4. There are 799 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1704 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKI	NM_003036.4	c.294C>T	p.Thr98=	synonymous_variant	1/7	ENST00000378536.5
SKI	XM_005244775.4	c.294C>T	p.Thr98=	synonymous_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKI	ENST00000378536.5	c.294C>T	p.Thr98=	synonymous_variant	1/7	1	NM_003036.4	P1
SKI	ENST00000704337.1	n.137+1536C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1702 AN: 152100 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00322 AC: 772 AN: 239722 Hom.: 13 AF XY: 0.00254 AC XY: 334 AN XY: 131590

Gnomad AFR exome AF: 0.0412

Gnomad AMR exome AF: 0.00277

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00268

GnomAD4 exome AF: 0.00124 AC: 1808 AN: 1454260 Hom.: 25 Cov.: 33 AF XY: 0.00107 AC XY: 774 AN XY: 723828

Gnomad4 AFR exome AF: 0.0396

Gnomad4 AMR exome AF: 0.00327

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000216

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.00292

GnomAD4 genome AF: 0.0112 AC: 1704 AN: 152218 Hom.: 33 Cov.: 32 AF XY: 0.0107 AC XY: 799 AN XY: 74430

Gnomad4 AFR AF: 0.0375

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.00321 Hom.: 2

Bravo AF: 0.0135

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	Jul 21, 2023	- -

Shprintzen-Goldberg syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.3
DANN	Benign	0.92
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: rs115746142; hg19: chr1-2160499;