chr1-2303939-C-T

Variant names:

• chr1-2303939-C-T
• rs140889128
• NM_003036.4:c.1311C>T

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.1311C>T​(p.Ala437Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,611,696 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A437A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0078 (10 hom., cov: 32)
  • Exomes 𝑓: 0.010 (88 hom.)
• Consequence: SKI NM_003036.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -2.64
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, 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=-0.72).
• BP6: Variant 1-2303939-C-T is Benign according to our data. Variant chr1-2303939-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.64 with no splicing effect.
• BS2: High AC in GnomAd4 at 1182 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.1311C>T	p.Ala437Ala	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.1311C>T	p.Ala437Ala	synonymous	Exon 4 of 7	ENSP00000367797.4	P12755
	SKI	ENST00000851187.1		c.1311C>T	p.Ala437Ala	synonymous	Exon 4 of 7	ENSP00000521247.1
	SKI	ENST00000507179.1	TSL:2	n.294C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00776 AC: 1181 AN: 152188 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00998

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.00784 AC: 1883 AN: 240128 AF XY: 0.00781

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00384

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0182

Gnomad NFE exome AF: 0.00896

Gnomad OTH exome AF: 0.00945

GnomAD4 exome AF: 0.0104 AC: 15243 AN: 1459390 Hom.: 88 Cov.: 32 AF XY: 0.0101 AC XY: 7342 AN XY: 726018

African (AFR) AF: 0.00176 AC: 59 AN: 33468

American (AMR) AF: 0.00433 AC: 193 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 561 AN: 26088

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39668

South Asian (SAS) AF: 0.00364 AC: 314 AN: 86174

European-Finnish (FIN) AF: 0.0171 AC: 889 AN: 51850

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5756

European-Non Finnish (NFE) AF: 0.0114 AC: 12626 AN: 1111536

Other (OTH) AF: 0.00955 AC: 575 AN: 60228

GnomAD4 genome AF: 0.00776 AC: 1182 AN: 152306 Hom.: 10 Cov.: 32 AF XY: 0.00782 AC XY: 582 AN XY: 74468

African (AFR) AF: 0.00224 AC: 93 AN: 41570

American (AMR) AF: 0.00660 AC: 101 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00725 AC: 35 AN: 4830

European-Finnish (FIN) AF: 0.0162 AC: 172 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0100 AC: 680 AN: 68022

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00568 Hom.: 0

Bravo AF: 0.00696

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0115

EpiControl AF: 0.00855

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	3	Shprintzen-Goldberg syndrome (3)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.9
DANN	Benign	0.67
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140889128; hg19: chr1-2235378;