rs28384811

chr1-2228951-C-G

Variant summary

Our verdict is Benign. Variant got -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. 13/19 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:11
• Conservation: PhyloP100: 1.59

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 139113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2228951-C-G is described in Lovd as [Benign]. Variant chr1-2228951-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKI	NM_003036.4	c.185C>G	p.Ala62Gly	missense_variant	1/7	ENST00000378536.5
SKI	XM_005244775.4	c.185C>G	p.Ala62Gly	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKI	ENST00000378536.5	c.185C>G	p.Ala62Gly	missense_variant	1/7	1	NM_003036.4	P1
SKI	ENST00000704337.1	n.137+1427C>G		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.0877 AC: 4816 AN: 54924 Hom.: 263 AF XY: 0.0899 AC XY: 2971 AN XY: 33050

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 SAS exome AF: 0.110

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

Gnomad4 AFR exome AF: 0.0281

Gnomad4 AMR exome AF: 0.0618

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.00432

Gnomad4 SAS exome AF: 0.0915

Gnomad4 FIN exome AF: 0.0414

Gnomad4 NFE exome AF: 0.0744

Gnomad4 OTH exome AF: 0.0729

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

Gnomad4 AFR AF: 0.0297

Gnomad4 AMR AF: 0.0574

Gnomad4 ASJ AF: 0.0949

Gnomad4 EAS AF: 0.00607

Gnomad4 SAS AF: 0.0767

Gnomad4 FIN AF: 0.0318

Gnomad4 NFE AF: 0.0693

Gnomad4 OTH AF: 0.0679

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

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ala62Gly in exon 1 of SKI: This variant is not expected to have clinical signifi cance because it has been identified in 10.6% (14/132) of Mexican chromosomes fr om a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/p rojects/SNP; dbSNP rs28384811). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Shprintzen-Goldberg syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 20, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	P
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

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

Publications

LitVar

Other links and lift over

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