1-2228951-C-G

Variant names:

• chr1-2228951-C-G
• rs28384811
• NM_003036.4:c.185C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003036.4(SKI):​c.185C>G​(p.Ala62Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 1,396,788 control chromosomes in the GnomAD database, including 3,804 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. A62S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.053 (290 hom., cov: 32)
  • Exomes 𝑓: 0.072 (3514 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.59
• Publications: 14 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: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017156601).
• BP6: Variant 1-2228951-C-G is Benign according to our data. Variant chr1-2228951-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0702 is higher than 0.05.

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.185C>G	p.Ala62Gly	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.185C>G	p.Ala62Gly	missense	Exon 1 of 7	ENSP00000367797.4	P12755
	SKI	ENST00000851187.1		c.185C>G	p.Ala62Gly	missense	Exon 1 of 7	ENSP00000521247.1
	SKI	ENST00000704337.1		n.137+1427C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0533 AC: 8011 AN: 150266 Hom.: 290 Cov.: 32

Gnomad AFR AF: 0.0298

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0576

Gnomad ASJ AF: 0.0949

Gnomad EAS AF: 0.00605

Gnomad SAS AF: 0.0760

Gnomad FIN AF: 0.0318

Gnomad MID AF: 0.151

Gnomad NFE AF: 0.0693

Gnomad OTH AF: 0.0687

GnomAD2 exomes AF: 0.0877 AC: 4816 AN: 54924 AF XY: 0.0899

Gnomad AFR exome AF: 0.0347

Gnomad AMR exome AF: 0.0680

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.0124

Gnomad FIN exome AF: 0.0415

Gnomad NFE exome AF: 0.0920

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0724 AC: 90238 AN: 1246414 Hom.: 3514 Cov.: 32 AF XY: 0.0737 AC XY: 45257 AN XY: 614398

African (AFR) AF: 0.0281 AC: 690 AN: 24576

American (AMR) AF: 0.0618 AC: 1059 AN: 17130

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2009 AN: 19902

East Asian (EAS) AF: 0.00432 AC: 113 AN: 26160

South Asian (SAS) AF: 0.0915 AC: 5762 AN: 62994

European-Finnish (FIN) AF: 0.0414 AC: 1299 AN: 31392

Middle Eastern (MID) AF: 0.123 AC: 476 AN: 3862

European-Non Finnish (NFE) AF: 0.0744 AC: 75165 AN: 1010124

Other (OTH) AF: 0.0729 AC: 3665 AN: 50274

GnomAD4 genome AF: 0.0533 AC: 8009 AN: 150374 Hom.: 290 Cov.: 32 AF XY: 0.0510 AC XY: 3746 AN XY: 73436

African (AFR) AF: 0.0297 AC: 1228 AN: 41338

American (AMR) AF: 0.0574 AC: 869 AN: 15132

Ashkenazi Jewish (ASJ) AF: 0.0949 AC: 326 AN: 3436

East Asian (EAS) AF: 0.00607 AC: 31 AN: 5110

South Asian (SAS) AF: 0.0767 AC: 370 AN: 4826

European-Finnish (FIN) AF: 0.0318 AC: 316 AN: 9922

Middle Eastern (MID) AF: 0.152 AC: 44 AN: 290

European-Non Finnish (NFE) AF: 0.0693 AC: 4665 AN: 67320

Other (OTH) AF: 0.0679 AC: 142 AN: 2090

Alfa AF: 0.0583 Hom.: 39

Bravo AF: 0.0544

TwinsUK AF: 0.0752 AC: 279

ALSPAC AF: 0.0706 AC: 272

ExAC AF: 0.0314 AC: 1578

Asia WGS AF: 0.0290 AC: 100 AN: 3426

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.037
Eigen_PC	Benign	-0.050
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.20
Sift	Uncertain	0.017	D
Sift4G	Benign	0.47	T
Polyphen		0.98	D
Vest4		0.10
MPC		1.6
ClinPred		0.021	T
GERP RS		2.3
Varity_R		0.074
gMVP		0.39
Mutation Taster		=99/1	polymorphism (auto)

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: rs28384811; hg19: chr1-2160390; COSMIC: COSV66013939; COSMIC: COSV66013939;