Genetic Variant SKI:p.Lys48Gln (chr1-2228908-A-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_003036.4(SKI):c.142A>C(p.Lys48Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000142 in 1,411,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K48K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SKI
NM_003036.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 4.23

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3511362).

BS2

High AC in GnomAd4 at 5 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.142A>C	p.Lys48Gln	missense	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.142A>C	p.Lys48Gln	missense	Exon 1 of 7	ENSP00000367797.4	P12755
SKI	ENST00000851187.1		c.142A>C	p.Lys48Gln	missense	Exon 1 of 7	ENSP00000521247.1
SKI	ENST00000704337.1		n.137+1384A>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000334

AC:

AN:

149590

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000746

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000116

AC:

AN:

86544

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000295

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000119

AC:

AN:

1261598

Hom.:

Cov.:

AF XY:

0.00000803

AC XY:

AN XY:

623042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25802

American (AMR)

AF:

0.00

AC:

AN:

24780

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20550

East Asian (EAS)

AF:

0.00

AC:

AN:

25254

South Asian (SAS)

AF:

0.00

AC:

AN:

69658

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31450

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3832

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

1010234

Other (OTH)

AF:

0.00

AC:

AN:

50038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.0000334

AC:

AN:

149590

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72942

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41092

American (AMR)

AF:

0.00

AC:

AN:

15084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3426

East Asian (EAS)

AF:

0.00

AC:

AN:

5094

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000746

AC:

AN:

67048

Other (OTH)

AF:

0.00

AC:

AN:

2054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Shprintzen-Goldberg syndrome (2)

Familial thoracic aortic aneurysm and aortic dissection (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.23

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.35

MetaSVM

Uncertain

0.096

MutationAssessor

Benign

0.55

PhyloP100

4.2

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.78

REVEL

Benign

0.27

Sift

Benign

0.33

Sift4G

Benign

0.61

Polyphen

0.42

Vest4

0.24

MVP

0.73

MPC

1.7

ClinPred

0.29

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.23

gMVP

0.59

Mutation Taster

=98/2

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over