rs730880212

Variant names:

• chr1-2304386-C-T
• rs730880212
• NM_003036.4:c.1568C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003036.4(SKI):​c.1568C>T​(p.Ser523Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000683 in 1,551,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S523A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -0.0770
• Publications: 1 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013550699).
• BP6: Variant 1-2304386-C-T is Benign according to our data. Variant chr1-2304386-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 180522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 12 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.1568C>T	p.Ser523Leu	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.1568C>T	p.Ser523Leu	missense	Exon 5 of 7	ENSP00000367797.4	P12755
	SKI	ENST00000851187.1		c.1574C>T	p.Ser525Leu	missense	Exon 5 of 7	ENSP00000521247.1
	SKI	ENST00000507179.1	TSL:2	n.*18C>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000179 AC: 28 AN: 156742 AF XY: 0.000169

Gnomad AFR exome AF: 0.000113

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00176

Gnomad EAS exome AF: 0.0000873

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.0000672 AC: 94 AN: 1399696 Hom.: 0 Cov.: 34 AF XY: 0.0000767 AC XY: 53 AN XY: 690558

African (AFR) AF: 0.0000316 AC: 1 AN: 31626

American (AMR) AF: 0.000139 AC: 5 AN: 35954

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 50 AN: 25182

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35778

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000269 AC: 29 AN: 1079512

Other (OTH) AF: 0.000121 AC: 7 AN: 58034

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74376

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000215 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.0000763 AC: 8

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.077
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.20
Sift	Benign	0.43	T
Sift4G	Benign	0.36	T
Polyphen		0.0010	B
Vest4		0.10
MVP		0.45
MPC		0.18
ClinPred		0.015	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.039
gMVP		0.080
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs730880212; hg19: chr1-2235825; COSMIC: COSV109438195; COSMIC: COSV109438195;