chr1-2304386-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 17/22 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

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Shprintzen-Goldberg syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Orphanet, Genomics England PanelApp, ClinGen

SKI links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 180522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003036.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKI	NM_003036.4	MANE Select	c.1568C>T	p.Ser523Leu	missense	Exon 5 of 7	NP_003027.1	P12755

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SKI	ENST00000378536.5	TSL:1 MANE Select	c.1568C>T	p.Ser523Leu	missense	Exon 5 of 7	ENSP00000367797.4	P12755
SKI	ENST00000851187.1		c.1574C>T	p.Ser525Leu	missense	Exon 5 of 7	ENSP00000521247.1
SKI	ENST00000507179.1	TSL:2	n.*18C>T		downstream_gene	N/A

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

GnomAD2 exomes

AF:

0.000179

AC:

AN:

156742

AF XY:

0.000169

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 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

African (AFR)

AF:

0.0000316

AC:

AN:

31626

American (AMR)

AF:

0.000139

AC:

AN:

35954

Ashkenazi Jewish (ASJ)

AF:

0.00199

AC:

AN:

25182

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35778

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79340

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000269

AC:

AN:

1079512

Other (OTH)

AF:

0.000121

AC:

AN:

58034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68034

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000215

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000763

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Arterial dissection (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

Shprintzen-Goldberg syndrome (1)

SKI-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

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

PhyloP100

-0.077

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

Mutation Taster

=98/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over