rs28384811

Positions:

chr1-2228951-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003036.4(SKI):c.185C>G(p.Ala62Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 1,396,788 control chromosomes in the GnomAD database, including 3,804 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A62S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.053 ( 290 hom., cov: 32)

Exomes 𝑓: 0.072 ( 3514 hom. )

Consequence

SKI
NM_003036.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.59

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017156601).

BP6

Variant 1-2228951-C-G is Benign according to our data. Variant chr1-2228951-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 139113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2228951-C-G is described in Lovd as [Benign]. Variant chr1-2228951-C-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKI	NM_003036.4 linkuse as main transcript	c.185C>G	p.Ala62Gly	missense_variant	1/7	ENST00000378536.5
SKI	XM_005244775.4 linkuse as main transcript	c.185C>G	p.Ala62Gly	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKI	ENST00000378536.5 linkuse as main transcript	c.185C>G	p.Ala62Gly	missense_variant	1/7	1	NM_003036.4	P1
SKI	ENST00000704337.1 linkuse as main transcript	n.137+1427C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0533

AC:

8011

AN:

150266

Hom.:

290

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0298

Gnomad AMI

AF:

0.0198

Gnomad AMR

AF:

0.0576

Gnomad ASJ

AF:

0.0949

Gnomad EAS

AF:

0.00605

Gnomad SAS

AF:

0.0760

Gnomad FIN

AF:

0.0318

Gnomad MID

AF:

0.151

Gnomad NFE

AF:

0.0693

Gnomad OTH

AF:

0.0687

GnomAD3 exomes

AF:

0.0877

AC:

4816

AN:

54924

Hom.:

263

AF XY:

0.0899

AC XY:

2971

AN XY:

33050

show subpopulations

Gnomad AFR exome

AF:

0.0347

Gnomad AMR exome

AF:

0.0680

Gnomad ASJ exome

AF:

0.107

Gnomad EAS exome

AF:

0.0124

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.0415

Gnomad NFE exome

AF:

0.0920

Gnomad OTH exome

AF:

0.103

GnomAD4 exome

AF:

0.0724

AC:

90238

AN:

1246414

Hom.:

3514

Cov.:

AF XY:

0.0737

AC XY:

45257

AN XY:

614398

show subpopulations

Gnomad4 AFR exome

AF:

0.0281

Gnomad4 AMR exome

AF:

0.0618

Gnomad4 ASJ exome

AF:

0.101

Gnomad4 EAS exome

AF:

0.00432

Gnomad4 SAS exome

AF:

0.0915

Gnomad4 FIN exome

AF:

0.0414

Gnomad4 NFE exome

AF:

0.0744

Gnomad4 OTH exome

AF:

0.0729

GnomAD4 genome

AF:

0.0533

AC:

8009

AN:

150374

Hom.:

290

Cov.:

AF XY:

0.0510

AC XY:

3746

AN XY:

73436

show subpopulations

Gnomad4 AFR

AF:

0.0297

Gnomad4 AMR

AF:

0.0574

Gnomad4 ASJ

AF:

0.0949

Gnomad4 EAS

AF:

0.00607

Gnomad4 SAS

AF:

0.0767

Gnomad4 FIN

AF:

0.0318

Gnomad4 NFE

AF:

0.0693

Gnomad4 OTH

AF:

0.0679

Alfa

AF:

0.0583

Hom.:

Bravo

AF:

0.0544

TwinsUK

AF:

0.0752

AC:

279

ALSPAC

AF:

0.0706

AC:

272

ExAC

AF:

0.0314

AC:

1578

Asia WGS

AF:

0.0290

AC:

100

AN:

3426

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ala62Gly in exon 1 of SKI: This variant is not expected to have clinical signifi cance because it has been identified in 10.6% (14/132) of Mexican chromosomes fr om a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/p rojects/SNP; dbSNP rs28384811). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 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. -
Likely 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	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Shprintzen-Goldberg syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 20, 2023	- -
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	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2014

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

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.21

Eigen

Benign

-0.037

Eigen_PC

Benign

-0.050

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.30

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.14

REVEL

Benign

0.20

Sift

Uncertain

0.017

Sift4G

Benign

0.47

Polyphen

0.98

Vest4

0.10

MPC

1.6

ClinPred

0.021

GERP RS

2.3

Varity_R

0.074

gMVP

0.39

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