1-2228869-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_003036.4(SKI):c.103C>T(p.Pro35Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000078 in 1,281,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P35R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.8e-7 ( 0 hom. )

Consequence

SKI
NM_003036.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.81

Publications

4 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: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003036.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-2228870-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 409977.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.919

PP5

Variant 1-2228869-C-T is Pathogenic according to our data. Variant chr1-2228869-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 39786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKI	NM_003036.4 link	c.103C>T	p.Pro35Ser	missense_variant	Exon 1 of 7	ENST00000378536.5	NP_003027.1	P12755
SKI	XM_005244775.4 link	c.103C>T	p.Pro35Ser	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.103C>T	p.Pro35Ser	missense_variant	Exon 1 of 7	1	NM_003036.4	ENSP00000367797.4		P12755
SKI	ENST00000704337.1 link	n.137+1345C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.80e-7

AC:

AN:

1281366

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

633380

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26286

American (AMR)

AF:

0.00

AC:

AN:

26428

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21090

East Asian (EAS)

AF:

0.00

AC:

AN:

26544

South Asian (SAS)

AF:

0.00

AC:

AN:

72252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31854

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3752

European-Non Finnish (NFE)

AF:

9.79e-7

AC:

AN:

1021906

Other (OTH)

AF:

0.00

AC:

AN:

51254

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Shprintzen-Goldberg syndrome

Pathogenic:5

Feb 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 39786). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro35 amino acid residue in SKI. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23103230). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt SKI protein function. This missense change has been observed in individual(s) with Shprintzen-Goldberg syndrome (PMID: 23023332, 23103230, 24357594, 24736733). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 35 of the SKI protein (p.Pro35Ser). -

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 01, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jul 12, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4, PM1, PM2, PM5, PP3 - This variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 39786). Not observed in large population cohorts (gnomAD). It has been previously reported as causative for Shprintzen-Goldberg syndrome (PMID: 23103230, 24357594) -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

May 23, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.103C>T (p.P35S) alteration is located in exon 1 (coding exon 1) of the SKI gene. This alteration results from a C to T substitution at nucleotide position 103, causing the proline (P) at amino acid position 35 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The c.103C>T alteration has been reported in individuals with features consistent with Shprintzen-Goldberg syndrome (Yoon, 2020) and was reported to be de novo in three individuals (Carmignac, 2012; Au, 2014; Schepers, 2015). This amino acid position is highly conserved in available vertebrate species with limited alignment for this region. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.3

PhyloP100

6.8

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.82

MutPred

0.40

Gain of MoRF binding (P = 0.0438);

MVP

0.98

MPC

1.5

ClinPred

0.99

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.91

gMVP

0.81

Mutation Taster

=28/72

disease causing (ClinVar)

(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