1-2228865-C-G

Position:

chr1-2228865-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_003036.4(SKI):c.99C>G(p.Gly33=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,428,256 control chromosomes in the GnomAD database, including 365 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. G33G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 27 hom., cov: 31)

Exomes 𝑓: 0.021 ( 338 hom. )

Consequence

SKI
NM_003036.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.911

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 1-2228865-C-G is Benign according to our data. Variant chr1-2228865-C-G is described in ClinVar as [Benign]. Clinvar id is 139112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2228865-C-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.911 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0134 (2005/149744) while in subpopulation NFE AF= 0.0213 (1429/67008). AF 95% confidence interval is 0.0204. There are 27 homozygotes in gnomad4. There are 932 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2005 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKI	NM_003036.4 linkuse as main transcript	c.99C>G	p.Gly33=	synonymous_variant	1/7	ENST00000378536.5
SKI	XM_005244775.4 linkuse as main transcript	c.99C>G	p.Gly33=	synonymous_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKI	ENST00000378536.5 linkuse as main transcript	c.99C>G	p.Gly33=	synonymous_variant	1/7	1	NM_003036.4	P1
SKI	ENST00000704337.1 linkuse as main transcript	n.137+1341C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0134

AC:

2005

AN:

149638

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.0126

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.0153

Gnomad MID

AF:

0.0160

Gnomad NFE

AF:

0.0213

Gnomad OTH

AF:

0.0170

GnomAD3 exomes

AF:

0.0133

AC:

1267

AN:

95400

Hom.:

AF XY:

0.0129

AC XY:

701

AN XY:

54486

show subpopulations

Gnomad AFR exome

AF:

0.00284

Gnomad AMR exome

AF:

0.00946

Gnomad ASJ exome

AF:

0.0156

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00532

Gnomad FIN exome

AF:

0.0187

Gnomad NFE exome

AF:

0.0198

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0214

AC:

27383

AN:

1278512

Hom.:

338

Cov.:

AF XY:

0.0210

AC XY:

13258

AN XY:

631882

show subpopulations

Gnomad4 AFR exome

AF:

0.00293

Gnomad4 AMR exome

AF:

0.0107

Gnomad4 ASJ exome

AF:

0.0156

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00504

Gnomad4 FIN exome

AF:

0.0165

Gnomad4 NFE exome

AF:

0.0243

Gnomad4 OTH exome

AF:

0.0189

GnomAD4 genome

AF:

0.0134

AC:

2005

AN:

149744

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

932

AN XY:

73052

show subpopulations

Gnomad4 AFR

AF:

0.00366

Gnomad4 AMR

AF:

0.0109

Gnomad4 ASJ

AF:

0.0126

Gnomad4 EAS

AF:

0.000196

Gnomad4 SAS

AF:

0.00478

Gnomad4 FIN

AF:

0.0153

Gnomad4 NFE

AF:

0.0213

Gnomad4 OTH

AF:

0.0168

Alfa

AF:

0.0173

Hom.:

Bravo

AF:

0.0138

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 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)	Jan 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2015	p.Gly33Gly in exon 1 of SKI: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 1.8% (248/13094) of p an ethnic chromosomes including two homozygous individuals by the Exome Aggregat ion Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs200019352). -
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	Genetic Services Laboratory, University of Chicago	Jul 14, 2018	- -

Shprintzen-Goldberg syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 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

-0.64

CADD

Benign

DANN

Benign

0.69

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over