rs397514590

Positions:

• chr1-2228869-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_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. P35Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.81

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a helix (size 4) in uniprot entity SKI_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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-A is described in Lovd as [Pathogenic].
• 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 id is 39786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2228869-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-2228869-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKI	NM_003036.4	c.103C>T	p.Pro35Ser	missense_variant	1/7	ENST00000378536.5	NP_003027.1
SKI	XM_005244775.4	c.103C>T	p.Pro35Ser	missense_variant	1/7		XP_005244832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKI	ENST00000378536.5	c.103C>T	p.Pro35Ser	missense_variant	1/7	1	NM_003036.4	ENSP00000367797	P1
SKI	ENST00000704337.1	n.137+1345C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.80e-7 AC: 1 AN: 1281366 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 633380

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.79e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Shprintzen-Goldberg syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 20, 2023	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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 39786). 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 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Jul 12, 2024	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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

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	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.40		Gain of MoRF binding (P = 0.0438);
MVP		0.98
MPC		1.5
ClinPred		0.99	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.91
gMVP		0.81

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

Other links and lift over

dbSNP: rs397514590; hg19: chr1-2160308;