chr1-2306743-G-C

Variant names:

• chr1-2306743-G-C
• rs1488554459
• NM_003036.4:c.2165G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003036.4(SKI):​c.2165G>C​(p.Gly722Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 1,373,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G722D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.77
• 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, PanelApp Australia, G2P, Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15133846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKI	NM_003036.4	c.2165G>C	p.Gly722Ala	missense_variant	Exon 7 of 7	ENST00000378536.5	NP_003027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SKI	ENST00000378536.5	c.2165G>C	p.Gly722Ala	missense_variant	Exon 7 of 7	1	NM_003036.4	ENSP00000367797.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000218 AC: 3 AN: 1373912 Hom.: 0 Cov.: 32 AF XY: 0.00000148 AC XY: 1 AN XY: 677428

African (AFR) AF: 0.000104 AC: 3 AN: 28910

American (AMR) AF: 0.00 AC: 0 AN: 34198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24386

East Asian (EAS) AF: 0.00 AC: 0 AN: 33908

South Asian (SAS) AF: 0.00 AC: 0 AN: 77326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071472

Other (OTH) AF: 0.00 AC: 0 AN: 56850

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	0.0091	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	15
DANN	Benign	0.65
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	0.78	T
Vest4		0.11
ClinPred		0.080	T
GERP RS		4.2
Varity_R		0.057
gMVP		0.22
Mutation Taster		=99/1	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: rs1488554459; hg19: chr1-2238182;