1-2228778-G-GGCAGGCGGCC

Position:

• chr1-2228778-G-GGCAGGCGGCC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_003036.4(SKI):​c.15_24dupAGGCGGCCGC​(p.Gly9fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. 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. G9G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SKI NM_003036.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 59 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKI	NM_003036.4	c.15_24dupAGGCGGCCGC	p.Gly9fs	frameshift_variant	1/7	ENST00000378536.5	NP_003027.1
SKI	XM_005244775.4	c.15_24dupAGGCGGCCGC	p.Gly9fs	frameshift_variant	1/7		XP_005244832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKI	ENST00000378536.5	c.15_24dupAGGCGGCCGC	p.Gly9fs	frameshift_variant	1/7	1	NM_003036.4	ENSP00000367797.4
SKI	ENST00000704337.1	n.137+1257_137+1266dupAGGCGGCCGC		intron_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 22, 2018

The c.15_24dup10 variant in the SKI gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.15_24dup10 variant causes a frameshift starting with codon Glycine 9, changes this amino acid to a Arginine residue, and creates a premature Stop codon at position 224 of the new reading frame, denoted p.Gly9ArgfsX224. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.15_24dup10 variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.15_24dup10 as a variant of uncertain significance, which may be related to the developmental delay and mild dysmorphic features reported in this individual. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553189805; hg19: chr1-2160217;