rs114345135

Variant names:

• chr1-2304074-G-A
• rs114345135
• NM_003036.4:c.1446G>A
• SKI p.Ala482Ala

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003036.4(SKI):​c.1446G>A​(p.Ala482Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00839 in 1,612,576 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (60 hom.)
• Consequence: SKI NM_003036.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -3.23
• Publications: 3 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-2304074-G-A is Benign according to our data. Variant chr1-2304074-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.23 with no splicing effect.
• BS2: High AC in GnomAd4 at 847 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.1446G>A	p.Ala482Ala	synonymous	Exon 4 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.1446G>A	p.Ala482Ala	synonymous	Exon 4 of 7	ENSP00000367797.4	P12755
	SKI	ENST00000851187.1		c.1446G>A	p.Ala482Ala	synonymous	Exon 4 of 7	ENSP00000521247.1
	SKI	ENST00000507179.1	TSL:2	n.429G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00557 AC: 848 AN: 152214 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00988

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00908

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00568 AC: 1397 AN: 245914 AF XY: 0.00546

Gnomad AFR exome AF: 0.00145

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.000603

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00989

Gnomad NFE exome AF: 0.00883

Gnomad OTH exome AF: 0.00530

GnomAD4 exome AF: 0.00868 AC: 12679 AN: 1460244 Hom.: 60 Cov.: 32 AF XY: 0.00851 AC XY: 6180 AN XY: 726416

African (AFR) AF: 0.00137 AC: 46 AN: 33468

American (AMR) AF: 0.00295 AC: 132 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.000613 AC: 16 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00182 AC: 157 AN: 86244

European-Finnish (FIN) AF: 0.00970 AC: 505 AN: 52082

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5722

European-Non Finnish (NFE) AF: 0.0102 AC: 11329 AN: 1111878

Other (OTH) AF: 0.00805 AC: 486 AN: 60340

GnomAD4 genome AF: 0.00556 AC: 847 AN: 152332 Hom.: 4 Cov.: 32 AF XY: 0.00517 AC XY: 385 AN XY: 74486

African (AFR) AF: 0.00183 AC: 76 AN: 41574

American (AMR) AF: 0.00196 AC: 30 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

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

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00988 AC: 105 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00907 AC: 617 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00772 Hom.: 2

Bravo AF: 0.00504

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00845

EpiControl AF: 0.00824

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	Shprintzen-Goldberg syndrome (3)
-	-	2	not provided (2)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	1.2
DANN	Benign	0.54
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs114345135;

hg19: chr1-2235513;