1-2304386-C-T

Position:

chr1-2304386-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003036.4(SKI):c.1568C>T(p.Ser523Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000683 in 1,551,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. S523A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

SKI
NM_003036.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:3

Conservation

PhyloP100: -0.0770

Variant links:

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 links:

SKI (HGNC:):

SKI links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013550699).

BP6

Variant 1-2304386-C-T is Benign according to our data. Variant chr1-2304386-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 180522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKI	NM_003036.4 linkuse as main transcript	c.1568C>T	p.Ser523Leu	missense_variant	5/7	ENST00000378536.5	NP_003027.1	P12755

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKI	ENST00000378536.5 linkuse as main transcript	c.1568C>T	p.Ser523Leu	missense_variant	5/7	1	NM_003036.4	ENSP00000367797.4		P12755
SKI	ENST00000507179.1 linkuse as main transcript	n.*18C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000179

AC:

AN:

156742

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

82736

show subpopulations

Gnomad AFR exome

AF:

0.000113

Gnomad AMR exome

AF:

0.000120

Gnomad ASJ exome

AF:

0.00176

Gnomad EAS exome

AF:

0.0000873

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000116

Gnomad OTH exome

AF:

0.000226

GnomAD4 exome

AF:

0.0000672

AC:

AN:

1399696

Hom.:

Cov.:

AF XY:

0.0000767

AC XY:

AN XY:

690558

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.000139

Gnomad4 ASJ exome

AF:

0.00199

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000269

Gnomad4 OTH exome

AF:

0.000121

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000215

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000763

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arterial dissection

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Oct 06, 2014

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 18, 2017

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. -

SKI-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Shprintzen-Goldberg syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.23

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.50

M_CAP

Benign

0.064

MetaRNN

Benign

0.014

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.5

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.3

REVEL

Benign

0.20

Sift

Benign

0.43

Sift4G

Benign

0.36

Polyphen

0.0010

Vest4

0.10

MVP

0.45

MPC

0.18

ClinPred

0.015

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.039

gMVP

0.080

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over