rs150985728

Positions:

• chr1-2304038-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.1410C>T​(p.Pro470Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000559 in 1,612,438 control chromosomes in the GnomAD database, including 4 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. P470P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (3 hom.)
• Consequence: SKI NM_003036.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -5.28

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=-0.78).
• BP6: Variant 1-2304038-C-T is Benign according to our data. Variant chr1-2304038-C-T is described in ClinVar as [Benign]. Clinvar id is 213673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2304038-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-5.28 with no splicing effect.
• BS2: High AC in GnomAd4 at 452 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKI	NM_003036.4	c.1410C>T	p.Pro470Pro	synonymous_variant	4/7	ENST00000378536.5	NP_003027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKI	ENST00000378536.5	c.1410C>T	p.Pro470Pro	synonymous_variant	4/7	1	NM_003036.4	ENSP00000367797.4
SKI	ENST00000507179.1	n.393C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 452 AN: 152212 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.000808 AC: 198 AN: 245178 Hom.: 3 AF XY: 0.000516 AC XY: 69 AN XY: 133726

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.000436

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000640

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000308 AC: 449 AN: 1460108 Hom.: 3 Cov.: 32 AF XY: 0.000288 AC XY: 209 AN XY: 726354

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.000614

GnomAD4 genome AF: 0.00297 AC: 452 AN: 152330 Hom.: 1 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74482

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00320

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2015	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:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 29, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.12
DANN	Benign	0.59

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: rs150985728; hg19: chr1-2235477; COSMIC: COSV66013928; COSMIC: COSV66013928;