Genetic Variant NM_003036.4:c.1475-60C>T (chr1-2304233-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003036.4(SKI):c.1475-60C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,552,814 control chromosomes in the GnomAD database, including 33,893 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 7559 hom., cov: 33)

Exomes 𝑓: 0.18 ( 26334 hom. )

Consequence

SKI
NM_003036.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.915

Publications

12 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, PanelApp Australia, G2P, Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

SKI links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 1-2304233-C-T is Benign according to our data. Variant chr1-2304233-C-T is described in ClinVar as Benign. ClinVar VariationId is 673795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKI	NM_003036.4 link	c.1475-60C>T		intron_variant	Intron 4 of 6	ENST00000378536.5	NP_003027.1	P12755

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SKI	ENST00000378536.5 link	c.1475-60C>T		intron_variant	Intron 4 of 6	1	NM_003036.4	ENSP00000367797.4		P12755
SKI	ENST00000507179.1 link	n.464-60C>T		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.275

AC:

41720

AN:

151928

Hom.:

7540

Cov.:

show subpopulations

Gnomad AFR

AF:

0.502

Gnomad AMI

AF:

0.164

Gnomad AMR

AF:

0.304

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.298

Gnomad SAS

AF:

0.344

Gnomad FIN

AF:

0.172

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.149

Gnomad OTH

AF:

0.248

GnomAD4 exome

AF:

0.175

AC:

245719

AN:

1400772

Hom.:

26334

Cov.:

AF XY:

0.178

AC XY:

123260

AN XY:

691230

show subpopulations

African (AFR)

AF:

0.517

AC:

16352

AN:

31628

American (AMR)

AF:

0.371

AC:

13292

AN:

35780

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

3563

AN:

25148

East Asian (EAS)

AF:

0.275

AC:

9827

AN:

35792

South Asian (SAS)

AF:

0.321

AC:

25512

AN:

79546

European-Finnish (FIN)

AF:

0.168

AC:

8276

AN:

49284

Middle Eastern (MID)

AF:

0.122

AC:

693

AN:

5682

European-Non Finnish (NFE)

AF:

0.145

AC:

157040

AN:

1079814

Other (OTH)

AF:

0.192

AC:

11164

AN:

58098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

11476

22952

34429

45905

57381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6044

12088

18132

24176

30220

<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:

0.275

AC:

41787

AN:

152042

Hom.:

7559

Cov.:

AF XY:

0.280

AC XY:

20782

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.502

AC:

20784

AN:

41440

American (AMR)

AF:

0.305

AC:

4660

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

476

AN:

3466

East Asian (EAS)

AF:

0.298

AC:

1535

AN:

5158

South Asian (SAS)

AF:

0.342

AC:

1649

AN:

4820

European-Finnish (FIN)

AF:

0.172

AC:

1820

AN:

10606

Middle Eastern (MID)

AF:

0.129

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.149

AC:

10152

AN:

67948

Other (OTH)

AF:

0.248

AC:

524

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1415

2830

4244

5659

7074

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

404

808

1212

1616

2020

<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:

0.175

Hom.:

4064

Bravo

AF:

0.294

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 18, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.78

(source)

DANN

Benign

0.62

PhyloP100

-0.92

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over