1-2228882-C-T

Position:

• chr1-2228882-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP3 BS2

The NM_003036.4(SKI):​c.116C>T​(p.Ser39Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000235 in 1,277,644 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S39S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.63

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 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, 6 uncertain in NM_003036.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756
• BS2: High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKI	NM_003036.4	c.116C>T	p.Ser39Leu	missense_variant	1/7	ENST00000378536.5	NP_003027.1
SKI	XM_005244775.4	c.116C>T	p.Ser39Leu	missense_variant	1/7		XP_005244832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKI	ENST00000378536.5	c.116C>T	p.Ser39Leu	missense_variant	1/7	1	NM_003036.4	ENSP00000367797.4
SKI	ENST00000704337.1	n.137+1358C>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000105 AC: 1 AN: 94856 Hom.: 0 AF XY: 0.0000184 AC XY: 1 AN XY: 54260

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000263

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000235 AC: 30 AN: 1277644 Hom.: 0 Cov.: 31 AF XY: 0.0000190 AC XY: 12 AN XY: 631492

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: 0.0000294

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.0000101 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 10, 2024

The p.S39L variant (also known as c.116C>T), located in coding exon 1 of the SKI gene, results from a C to T substitution at nucleotide position 116. The serine at codon 39 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Shprintzen-Goldberg syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2023

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 39 of the SKI protein (p.Ser39Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 463393). 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. 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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	0.12
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	1.3	L
PrimateAI	Pathogenic	0.97	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.13	T
Polyphen		0.99	D
Vest4		0.56
MutPred		0.47		Loss of disorder (P = 0.0301);
MVP		0.88
MPC		1.3
ClinPred		0.95	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.62
gMVP		0.72

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: rs746485528; hg19: chr1-2160321;