1-2228866-G-C

Variant names:

• chr1-2228866-G-C
• NM_003036.4:c.100G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_003036.4(SKI):​c.100G>C​(p.Gly34Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. G34C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.60

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 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr1-2228866-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 37262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 1-2228866-G-C is Pathogenic according to our data. Variant chr1-2228866-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2225761.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKI	NM_003036.4	c.100G>C	p.Gly34Arg	missense_variant	Exon 1 of 7	ENST00000378536.5	NP_003027.1
SKI	XM_005244775.4	c.100G>C	p.Gly34Arg	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	c.100G>C	p.Gly34Arg	missense_variant	Exon 1 of 7	1	NM_003036.4	ENSP00000367797.4
SKI	ENST00000704337.1	n.137+1342G>C		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Sep 09, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.100G>C (p.G34R) alteration is located in exon 1 (coding exon 1) of the SKI gene. This alteration results from a G to C substitution at nucleotide position 100, causing the glycine (G) at amino acid position 34 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Alterations affecting the same amino acid, p.G34S, p.G34D, p.G34A, p.G34C, p.G34V, have been reported in patients with Shprintzen-Goldberg syndrome (Carmignac, 2012; Doyle, 2012; Schepers, 2015). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional studies showed that the SKI p.G34R mutant abolishes binding to phosphorylated SMAD2 and SMAD3 resulting in attenuation of TGF-β induced transcriptional responses (Gori, 2021). This alteration is predicted to be deleterious by in silico analysis. 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	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	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	0.96	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.3	L
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.54		Gain of MoRF binding (P = 0.0029);
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.96
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-2160305;