rs1021794039

Variant names:

• chr1-2306639-C-A
• rs1021794039
• NM_003036.4:c.2061C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-2306639-C-A
• chr1-2306639-C-T
• chr1-2306639-C-G

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.2061C>A​(p.Asp687Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,392,286 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. D687G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.21
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09373647).

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.2061C>A	p.Asp687Glu	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.2061C>A	p.Asp687Glu	missense	Exon 7 of 7	ENSP00000367797.4	P12755
	SKI	ENST00000851187.1		c.2067C>A	p.Asp689Glu	missense	Exon 7 of 7	ENSP00000521247.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000722 AC: 1 AN: 138422 AF XY: 0.0000134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000203

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1392286 Hom.: 0 Cov.: 32 AF XY: 0.00000291 AC XY: 2 AN XY: 686756

African (AFR) AF: 0.00 AC: 0 AN: 31186

American (AMR) AF: 0.00 AC: 0 AN: 35556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25006

East Asian (EAS) AF: 0.00 AC: 0 AN: 35496

South Asian (SAS) AF: 0.00 AC: 0 AN: 78832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5080

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077254

Other (OTH) AF: 0.00 AC: 0 AN: 57724

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	Shprintzen-Goldberg syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.094	T
MetaSVM	Uncertain	-0.051	T
MutationAssessor	Benign	0.78	N
PhyloP100		1.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.27	N
REVEL	Uncertain	0.42
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.37	B
Vest4		0.18
MutPred		0.090		Gain of MoRF binding (P = 0.1963)
MVP		0.65
MPC		2.0
ClinPred		0.21	T
GERP RS		4.2
Varity_R		0.17
gMVP		0.37
Mutation Taster		=83/17	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: rs1021794039; hg19: chr1-2238078;