rs141862996

Variant names:

• chr1-2303385-C-T
• rs141862996
• NM_003036.4:c.1196C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003036.4(SKI):​c.1196C>T​(p.Ala399Val) variant causes a missense change. The variant allele was found at a frequency of 0.000296 in 1,613,072 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A399A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 5.07
• Publications: 4 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, PanelApp Australia, G2P, Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02307859).
• BP6: Variant 1-2303385-C-T is Benign according to our data. Variant chr1-2303385-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 213692.
• BS2: High AC in GnomAd4 at 210 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKI	NM_003036.4	MANE Select	c.1196C>T	p.Ala399Val	missense	Exon 3 of 7	NP_003027.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKI	ENST00000378536.5	TSL:1 MANE Select	c.1196C>T	p.Ala399Val	missense	Exon 3 of 7	ENSP00000367797.4
	SKI	ENST00000704337.1		n.364C>T		non_coding_transcript_exon	Exon 3 of 4
	SKI	ENST00000478223.2	TSL:3	n.*9C>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152212 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00470

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000118

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000375 AC: 94 AN: 250702 AF XY: 0.000251

Gnomad AFR exome AF: 0.00475

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000970

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000183 AC: 267 AN: 1460742 Hom.: 2 Cov.: 32 AF XY: 0.000161 AC XY: 117 AN XY: 726720

African (AFR) AF: 0.00505 AC: 169 AN: 33470

American (AMR) AF: 0.000268 AC: 12 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52530

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000540 AC: 60 AN: 1111798

Other (OTH) AF: 0.000315 AC: 19 AN: 60376

GnomAD4 genome AF: 0.00138 AC: 210 AN: 152330 Hom.: 2 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74498

African (AFR) AF: 0.00466 AC: 194 AN: 41590

American (AMR) AF: 0.000392 AC: 6 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000868 Hom.: 0

Bravo AF: 0.00181

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000445 AC: 54

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.023	T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.54
Sift	Benign	0.18	T
Sift4G	Benign	0.35	T
Polyphen		0.99	D
Vest4		0.67
MVP		0.78
MPC		0.27
ClinPred		0.036	T
GERP RS		4.0
Varity_R		0.076
gMVP		0.45
Mutation Taster		=70/30	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: rs141862996; hg19: chr1-2234824;