NM_003036.4:c.185C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

Shprintzen-Goldberg syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, G2P, Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

SKI links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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 rank	MANE	Protein	UniProt
SKI	NM_003036.4 link	c.185C>G	p.Ala62Gly	missense_variant	Exon 1 of 7	ENST00000378536.5	NP_003027.1	P12755
SKI	XM_005244775.4 link	c.185C>G	p.Ala62Gly	missense_variant	Exon 1 of 7		XP_005244832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SKI	ENST00000378536.5 link	c.185C>G	p.Ala62Gly	missense_variant	Exon 1 of 7	1	NM_003036.4	ENSP00000367797.4		P12755
SKI	ENST00000704337.1 link	n.137+1427C>G		intron_variant	Intron 1 of 3

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

GnomAD2 exomes

AF:

0.0877

AC:

4816

AN:

54924

AF XY:

0.0899

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 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

African (AFR)

AF:

0.0281

AC:

690

AN:

24576

American (AMR)

AF:

0.0618

AC:

1059

AN:

17130

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

2009

AN:

19902

East Asian (EAS)

AF:

0.00432

AC:

113

AN:

26160

South Asian (SAS)

AF:

0.0915

AC:

5762

AN:

62994

European-Finnish (FIN)

AF:

0.0414

AC:

1299

AN:

31392

Middle Eastern (MID)

AF:

0.123

AC:

476

AN:

3862

European-Non Finnish (NFE)

AF:

0.0744

AC:

75165

AN:

1010124

Other (OTH)

AF:

0.0729

AC:

3665

AN:

50274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

4150

8300

12450

16600

20750

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2908

5816

8724

11632

14540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0533

AC:

8009

AN:

150374

Hom.:

290

Cov.:

AF XY:

0.0510

AC XY:

3746

AN XY:

73436

show subpopulations

African (AFR)

AF:

0.0297

AC:

1228

AN:

41338

American (AMR)

AF:

0.0574

AC:

869

AN:

15132

Ashkenazi Jewish (ASJ)

AF:

0.0949

AC:

326

AN:

3436

East Asian (EAS)

AF:

0.00607

AC:

AN:

5110

South Asian (SAS)

AF:

0.0767

AC:

370

AN:

4826

European-Finnish (FIN)

AF:

0.0318

AC:

316

AN:

9922

Middle Eastern (MID)

AF:

0.152

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0693

AC:

4665

AN:

67320

Other (OTH)

AF:

0.0679

AC:

142

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

378

755

1133

1510

1888

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 16, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Apr 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Shprintzen-Goldberg syndrome

Benign:3

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Dec 30, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

1.6

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

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over