chr1-2306086-C-T

Position:

• chr1-2306086-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_003036.4(SKI):​c.1834C>T​(p.Leu612Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00575 in 1,602,498 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (39 hom.)
• Consequence: SKI NM_003036.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.472

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-2306086-C-T is Benign according to our data. Variant chr1-2306086-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 139116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2306086-C-T is described in Lovd as [Benign]. Variant chr1-2306086-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.472 with no splicing effect.
• BS2: High AC in GnomAd4 at 612 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKI	NM_003036.4	c.1834C>T	p.Leu612Leu	synonymous_variant	6/7	ENST00000378536.5	NP_003027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKI	ENST00000378536.5	c.1834C>T	p.Leu612Leu	synonymous_variant	6/7	1	NM_003036.4	ENSP00000367797.4

Frequencies

GnomAD3 genomes AF: 0.00402 AC: 612 AN: 152246 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00633

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00354 AC: 802 AN: 226526 Hom.: 2 AF XY: 0.00360 AC XY: 443 AN XY: 123206

Gnomad AFR exome AF: 0.00102

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.00782

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000572

Gnomad FIN exome AF: 0.000786

Gnomad NFE exome AF: 0.00549

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00593 AC: 8600 AN: 1450134 Hom.: 39 Cov.: 32 AF XY: 0.00577 AC XY: 4153 AN XY: 720290

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00307

Gnomad4 ASJ exome AF: 0.00794

Gnomad4 EAS exome AF: 0.0000510

Gnomad4 SAS exome AF: 0.000511

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.00701

Gnomad4 OTH exome AF: 0.00535

GnomAD4 genome AF: 0.00402 AC: 612 AN: 152364 Hom.: 3 Cov.: 33 AF XY: 0.00366 AC XY: 273 AN XY: 74508

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00496

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00634

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00589 Hom.: 3

Bravo AF: 0.00396

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 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	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Leu612Leu in exon 6 of SKI: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.6% (54/8578) of Euro pean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs35833638). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 08, 2015	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SKI: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Shprintzen-Goldberg syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 20, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2015

This alteration is classified as likely 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
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.3
DANN	Benign	0.92

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: rs35833638; hg19: chr1-2237525;