1-2304323-C-G

Variant names:

• chr1-2304323-C-G
• rs1057520161
• NM_003036.4:c.1505C>G

Variant summary

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

The NM_003036.4(SKI):​c.1505C>G​(p.Pro502Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P502L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.51
• 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: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Ambry Genetics

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.1505C>G	p.Pro502Arg	missense	Exon 5 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.1505C>G	p.Pro502Arg	missense	Exon 5 of 7	ENSP00000367797.4	P12755
	SKI	ENST00000851187.1		c.1511C>G	p.Pro504Arg	missense	Exon 5 of 7	ENSP00000521247.1
	SKI	ENST00000507179.1	TSL:2	n.494C>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Shprintzen-Goldberg syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.5
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.029	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.35		Gain of MoRF binding (P = 0.0063)
MVP		0.74
MPC		0.80
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.27
gMVP		0.52
Mutation Taster		=51/49	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: rs1057520161; hg19: chr1-2235762;