rs750838146

Positions:

Variant summary

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

The ENST00000378536.5(SKI):c.2007C>G(p.Asp669Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 1,542,760 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. D669G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00074 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00062 ( 17 hom. )

Consequence

SKI
ENST00000378536.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.44

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:

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=0.0036275089).

BP6

Variant 1-2306585-C-G is Benign according to our data. Variant chr1-2306585-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 213699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2306585-C-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 112 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKI	NM_003036.4 linkuse as main transcript	c.2007C>G	p.Asp669Glu	missense_variant	7/7	ENST00000378536.5	NP_003027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKI	ENST00000378536.5 linkuse as main transcript	c.2007C>G	p.Asp669Glu	missense_variant	7/7	1	NM_003036.4	ENSP00000367797	P1

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.0282

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00165

AC:

224

AN:

135916

Hom.:

AF XY:

0.00165

AC XY:

122

AN XY:

73868

show subpopulations

Gnomad AFR exome

AF:

0.000154

Gnomad AMR exome

AF:

0.0000411

Gnomad ASJ exome

AF:

0.0235

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000474

Gnomad OTH exome

AF:

0.00222

GnomAD4 exome

AF:

0.000621

AC:

863

AN:

1390592

Hom.:

Cov.:

AF XY:

0.000595

AC XY:

408

AN XY:

686128

show subpopulations

Gnomad4 AFR exome

AF:

0.0000320

Gnomad4 AMR exome

AF:

0.0000281

Gnomad4 ASJ exome

AF:

0.0255

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000110

Gnomad4 OTH exome

AF:

0.00180

GnomAD4 genome

AF:

0.000736

AC:

112

AN:

152168

Hom.:

Cov.:

AF XY:

0.000659

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.0282

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.00231

Hom.:

Bravo

AF:

0.000756

ExAC

AF:

0.00111

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2019	This variant is associated with the following publications: (PMID: 25519456) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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

Oct 13, 2015

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. -

Shprintzen-Goldberg syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.58

DEOGEN2

Benign

0.20

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0036

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

0.42

MutationTaster

Benign

0.90

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.060

REVEL

Uncertain

0.30

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0050

Vest4

0.084

MutPred

0.13

Loss of MoRF binding (P = 0.1102);

MVP

0.58

MPC

1.0

ClinPred

0.010

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.38

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

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