Genetic Variant SKI:p.Pro77Ser (chr1-2228995-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003036.4(SKI):c.229C>T(p.Pro77Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P77P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SKI
NM_003036.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.88

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKI	NM_003036.4 link	c.229C>T	p.Pro77Ser	missense_variant	Exon 1 of 7	ENST00000378536.5	NP_003027.1
SKI	XM_005244775.4 link	c.229C>T	p.Pro77Ser	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.229C>T	p.Pro77Ser	missense_variant	Exon 1 of 7	1	NM_003036.4	ENSP00000367797.4
SKI	ENST00000704337.1 link	n.137+1471C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1402292

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

694518

African (AFR)

AF:

0.00

AC:

AN:

32056

American (AMR)

AF:

0.00

AC:

AN:

37848

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25328

East Asian (EAS)

AF:

0.00

AC:

AN:

36446

South Asian (SAS)

AF:

0.00

AC:

AN:

81310

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4948

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1089134

Other (OTH)

AF:

0.00

AC:

AN:

58416

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Shprintzen-Goldberg syndrome

Uncertain:1

Feb 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 77 of the SKI protein (p.Pro77Ser). 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SKI protein function. ClinVar contains an entry for this variant (Variation ID: 532219). This variant has not been reported in the literature in individuals affected with SKI-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.44

MetaSVM

Uncertain

-0.049

MutationAssessor

Benign

0.0

PhyloP100

3.9

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-2.4

REVEL

Uncertain

0.34

Sift

Benign

0.037

Sift4G

Benign

0.078

Polyphen

0.58

Vest4

0.41

MutPred

0.33

Gain of glycosylation at P77 (P = 0.0387);

MVP

0.76

MPC

1.5

ClinPred

0.61

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.20

gMVP

0.73

Mutation Taster

=64/36

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over