SKI p.Pro728Arg

Variant names:

• chr1-2306761-C-G
• rs372950890
• NM_003036.4:c.2183C>G
• SKI p.Pro728Arg

Your query was ambiguous. Multiple possible variants found:

• chr1-2306761-C-G
• chr1-2306761-CG-GT
• chr1-2306761-CG-GC
• chr1-2306761-CG-GA
• chr1-2306760-CC-AG
• chr1-2306760-CCG-AGA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003036.4(SKI):​c.2183C>G​(p.Pro728Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000198 in 1,513,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. P728L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38
• Publications: 2 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet, Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32427967).

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.2183C>G	p.Pro728Arg	missense	Exon 7 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.2183C>G	p.Pro728Arg	missense	Exon 7 of 7	ENSP00000367797.4	P12755
	SKI	ENST00000851187.1		c.2189C>G	p.Pro730Arg	missense	Exon 7 of 7	ENSP00000521247.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151994 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1361644 Hom.: 0 Cov.: 32 AF XY: 0.00000149 AC XY: 1 AN XY: 671234

African (AFR) AF: 0.00 AC: 0 AN: 27958

American (AMR) AF: 0.00 AC: 0 AN: 32620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23930

East Asian (EAS) AF: 0.00 AC: 0 AN: 32754

South Asian (SAS) AF: 0.00 AC: 0 AN: 76280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41002

Middle Eastern (MID) AF: 0.000250 AC: 1 AN: 3998

European-Non Finnish (NFE) AF: 9.37e-7 AC: 1 AN: 1066744

Other (OTH) AF: 0.00 AC: 0 AN: 56358

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151994 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74240

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2090

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	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.32	T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.6	L
PhyloP100		1.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.16
gMVP		0.43
Mutation Taster		=89/11	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs372950890;

hg19: chr1-2238200;