rs75280988

chr1-2303352-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003036.4(SKI):c.1163C>T(p.Ala388Val) variant causes a missense change. The variant allele was found at a frequency of 0.00567 in 1,613,740 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. A388T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (43 hom.)
• Consequence: SKI NM_003036.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.38

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008442789).
• BP6: Variant 1-2303352-C-T is Benign according to our data. Variant chr1-2303352-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 213668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2303352-C-T is described in Lovd as [Likely_benign]. Variant chr1-2303352-C-T is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 611 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKI	NM_003036.4	c.1163C>T	p.Ala388Val	missense_variant	3/7	ENST00000378536.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKI	ENST00000378536.5	c.1163C>T	p.Ala388Val	missense_variant	3/7	1	NM_003036.4	P1
SKI	ENST00000478223.2	n.270C>T		non_coding_transcript_exon_variant	3/3	3
SKI	ENST00000704337.1	n.331C>T		non_coding_transcript_exon_variant	3/4

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 611 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00566

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00427 AC: 1073 AN: 251244 Hom.: 3 AF XY: 0.00429 AC XY: 583 AN XY: 135818

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.00628

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.00585 AC: 8545 AN: 1461442 Hom.: 43 Cov.: 32 AF XY: 0.00560 AC XY: 4071 AN XY: 727040

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00449

Gnomad4 ASJ exome AF: 0.0145

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.000887

Gnomad4 NFE exome AF: 0.00669

Gnomad4 OTH exome AF: 0.00656

GnomAD4 genome AF: 0.00401 AC: 610 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00375 AC XY: 279 AN XY: 74474

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00738

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00566

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00591 Hom.: 3

Bravo AF: 0.00482

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00384 AC: 466

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2016	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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2023	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 26, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SKI: BS2 -
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)	-	- -

Shprintzen-Goldberg syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2017

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	0.080
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	20
Dann	Benign	0.97
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.24
Sift	Benign	0.30	T
Sift4G	Benign	0.29	T
Polyphen		0.38	B
Vest4		0.35
MVP		0.57
MPC		0.20
ClinPred		0.0075	T
GERP RS		3.1
Varity_R		0.021
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs75280988; hg19: chr1-2234791; COSMIC: COSV66013568; COSMIC: COSV66013568;