Genetic Variant SKI:p.Ala388Val (chr1-2303352-C-T) – ACMG Classification: Benign (-16 pts)

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.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. 15/22 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. 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 5.38

Publications

16 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=0.008442789).

BP6

Variant 1-2303352-C-T is Benign according to our data. Variant chr1-2303352-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 213668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 610 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.1163C>T	p.Ala388Val	missense	Exon 3 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.1163C>T	p.Ala388Val	missense	Exon 3 of 7	ENSP00000367797.4	P12755
SKI	ENST00000851187.1		c.1163C>T	p.Ala388Val	missense	Exon 3 of 7	ENSP00000521247.1
SKI	ENST00000478223.2	TSL:3	n.270C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.00401

AC:

611

AN:

152180

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00427

AC:

1073

AN:

251244

AF XY:

0.00429

show subpopulations

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 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.:

Cov.:

AF XY:

0.00560

AC XY:

4071

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.00131

AC:

AN:

33480

American (AMR)

AF:

0.00449

AC:

201

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0145

AC:

380

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000278

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000887

AC:

AN:

52998

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00669

AC:

7440

AN:

1111992

Other (OTH)

AF:

0.00656

AC:

396

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

452

903

1355

1806

2258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

274

548

822

1096

1370

<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:

0.00401

AC:

610

AN:

152298

Hom.:

Cov.:

AF XY:

0.00375

AC XY:

279

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41574

American (AMR)

AF:

0.00738

AC:

113

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00566

AC:

385

AN:

68014

Other (OTH)

AF:

0.00380

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

120

150

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:

0.00560

Hom.:

Bravo

AF:

0.00482

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.00384

AC:

466

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (5)

Shprintzen-Goldberg syndrome (3)

Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.28

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.0084

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.2

PhyloP100

5.4

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.99

REVEL

Benign

0.24

Sift

Benign

0.30

Sift4G

Benign

0.29

Polyphen

0.38

Vest4

0.35

MVP

0.57

MPC

0.20

ClinPred

0.0075

GERP RS

3.1

Varity_R

0.021

gMVP

0.32

Mutation Taster

=96/4

polymorphism

(source)

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

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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