1-2228788-C-G

Variant names:

• chr1-2228788-C-G
• rs1254990952
• NM_003036.4:c.22C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003036.4(SKI):​c.22C>G​(p.Arg8Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000086 in 1,163,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.886
• Publications: 0 publications found

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, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Orphanet, Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003036.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKI	NM_003036.4	MANE Select	c.22C>G	p.Arg8Gly	missense	Exon 1 of 7	NP_003027.1	P12755

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKI	ENST00000378536.5	TSL:1 MANE Select	c.22C>G	p.Arg8Gly	missense	Exon 1 of 7	ENSP00000367797.4	P12755
	SKI	ENST00000851187.1		c.22C>G	p.Arg8Gly	missense	Exon 1 of 7	ENSP00000521247.1
	SKI	ENST00000704337.1		n.137+1264C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.60e-7 AC: 1 AN: 1163210 Hom.: 0 Cov.: 31 AF XY: 0.00000175 AC XY: 1 AN XY: 571586

African (AFR) AF: 0.00 AC: 0 AN: 23546

American (AMR) AF: 0.00 AC: 0 AN: 22024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17904

East Asian (EAS) AF: 0.00 AC: 0 AN: 20142

South Asian (SAS) AF: 0.00 AC: 0 AN: 58184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3116

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 950522

Other (OTH) AF: 0.00 AC: 0 AN: 44286

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Shprintzen-Goldberg syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Benign	0.80
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.26	N
PhyloP100		0.89
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.010	D
Polyphen		0.96	D
Vest4		0.46
MutPred		0.28		Loss of methylation at R8 (P = 0.011)
MVP		0.77
MPC		1.8
ClinPred		0.35	T
GERP RS		0.70
PromoterAI		-0.018	Neutral
Varity_R		0.15
gMVP		0.52
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs1254990952; hg19: chr1-2160227;