Genetic Variant NM_003036.4:c.216C>T (chr1-2228982-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_003036.4(SKI):c.216C>T(p.Pro72Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,471,856 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P72P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00078 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

SKI
NM_003036.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 0.675

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 1-2228982-C-T is Benign according to our data. Variant chr1-2228982-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193249.

BP7

Synonymous conserved (PhyloP=0.675 with no splicing effect.

BS2

High AC in GnomAd4 at 118 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.216C>T	p.Pro72Pro	synonymous	Exon 1 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.216C>T	p.Pro72Pro	synonymous	Exon 1 of 7	ENSP00000367797.4	P12755
SKI	ENST00000851187.1		c.216C>T	p.Pro72Pro	synonymous	Exon 1 of 7	ENSP00000521247.1
SKI	ENST00000704337.1		n.137+1458C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000782

AC:

118

AN:

150936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000291

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000330

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00148

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.000760

AC:

AN:

100038

AF XY:

0.000665

show subpopulations

Gnomad AFR exome

AF:

0.00139

Gnomad AMR exome

AF:

0.000169

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00148

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00137

AC:

1812

AN:

1320920

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

864

AN XY:

652282

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

27324

American (AMR)

AF:

0.000414

AC:

AN:

28964

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23084

East Asian (EAS)

AF:

0.00

AC:

AN:

29622

South Asian (SAS)

AF:

0.000290

AC:

AN:

72300

European-Finnish (FIN)

AF:

0.0000585

AC:

AN:

34178

Middle Eastern (MID)

AF:

0.00357

AC:

AN:

4486

European-Non Finnish (NFE)

AF:

0.00163

AC:

1701

AN:

1046542

Other (OTH)

AF:

0.000937

AC:

AN:

54420

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

196

294

392

490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

0.000782

AC:

118

AN:

150936

Hom.:

Cov.:

AF XY:

0.000719

AC XY:

AN XY:

73686

show subpopulations

African (AFR)

AF:

0.000291

AC:

AN:

41240

American (AMR)

AF:

0.000330

AC:

AN:

15160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5124

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10168

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00148

AC:

100

AN:

67666

Other (OTH)

AF:

0.000481

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000643

Hom.:

Bravo

AF:

0.000808

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (3)

Shprintzen-Goldberg syndrome (2)

Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Mutation Taster

=100/0

polymorphism

(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

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