rs1085307767

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003036.4(SKI):c.11C>T(p.Ala4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,136,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000019 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SKI
NM_003036.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.829

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20184556).

BS2

High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKI	NM_003036.4 link	c.11C>T	p.Ala4Val	missense_variant	Exon 1 of 7	ENST00000378536.5	NP_003027.1
SKI	XM_005244775.4 link	c.11C>T	p.Ala4Val	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.11C>T	p.Ala4Val	missense_variant	Exon 1 of 7	1	NM_003036.4	ENSP00000367797.4
SKI	ENST00000704337.1 link	n.137+1253C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

147652

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000193

AC:

AN:

1136970

Hom.:

Cov.:

AF XY:

0.0000197

AC XY:

AN XY:

557400

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23010

American (AMR)

AF:

0.00

AC:

AN:

21078

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17166

East Asian (EAS)

AF:

0.00

AC:

AN:

18656

South Asian (SAS)

AF:

0.00

AC:

AN:

54710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3002

European-Non Finnish (NFE)

AF:

0.0000235

AC:

AN:

935012

Other (OTH)

AF:

0.00

AC:

AN:

42818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

147652

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71886

African (AFR)

AF:

0.00

AC:

AN:

40856

American (AMR)

AF:

0.00

AC:

AN:

14920

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3398

East Asian (EAS)

AF:

0.00

AC:

AN:

5058

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66256

Other (OTH)

AF:

0.00

AC:

AN:

2036

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 06, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The A4V variant of uncertain significance in the SKI gene has not been published as pathogenic or been reported as benign to our knowledge. Data from control individuals was not available to assess whether A4V may be a common benign variant in the general population. However, the A4V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. -

Shprintzen-Goldberg syndrome

Uncertain:1

Apr 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4 of the SKI protein (p.Ala4Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SKI-related conditions. ClinVar contains an entry for this variant (Variation ID: 426734). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SKI protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.19

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.60

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.20

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

-0.55

PhyloP100

0.83

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.25

REVEL

Uncertain

0.30

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.60

Vest4

0.14

MutPred

0.28

Loss of disorder (P = 0.0533);

MVP

0.86

MPC

1.5

ClinPred

0.14

PromoterAI

-0.011

Neutral

(source)

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

4.0

Varity_R

0.071

gMVP

0.27

Mutation Taster

=95/5

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over