rs559020511

Variant names:

• chr1-2229230-C-G
• rs559020511
• NM_003036.4:c.464C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_003036.4(SKI):​c.464C>G​(p.Ala155Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,606,578 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. A155S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 7.64
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 6 AD gene.

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.464C>G	p.Ala155Gly	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.464C>G	p.Ala155Gly	missense	Exon 1 of 7	ENSP00000367797.4	P12755
	SKI	ENST00000851187.1		c.464C>G	p.Ala155Gly	missense	Exon 1 of 7	ENSP00000521247.1
	SKI	ENST00000704337.1		n.137+1706C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152248 Hom.: 0 Cov.: 32

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000346 AC: 8 AN: 231154 AF XY: 0.0000316

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: 0.0000785

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000193 AC: 28 AN: 1454212 Hom.: 0 Cov.: 33 AF XY: 0.0000194 AC XY: 14 AN XY: 722912

African (AFR) AF: 0.00 AC: 0 AN: 33336

American (AMR) AF: 0.00 AC: 0 AN: 43800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39398

South Asian (SAS) AF: 0.00 AC: 0 AN: 85314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1109120

Other (OTH) AF: 0.0000166 AC: 1 AN: 60080

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152366 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74504

African (AFR) AF: 0.00 AC: 0 AN: 41598

American (AMR) AF: 0.00 AC: 0 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000416 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Shprintzen-Goldberg syndrome (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	SKI-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.76
Sift	Benign	0.063	T
Sift4G	Benign	0.087	T
Polyphen		0.99	D
Vest4		0.61
MutPred		0.59		Gain of sheet (P = 0.0827)
MVP		0.76
MPC		1.5
ClinPred		0.44	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.88
Mutation Taster		=41/59	disease causing

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: rs559020511; hg19: chr1-2160669;