Genetic Variant SKI:p.Pro35Gln (chr1-2228870-C-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate

The NM_003036.4(SKI):c.104C>A(p.Pro35Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P35R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SKI
NM_003036.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.81

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_003036.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-2228870-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 409977.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.924

PP5

Variant 1-2228870-C-A is Pathogenic according to our data. Variant chr1-2228870-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 39785.Status of the report is criteria_provided_single_submitter, 1 stars.

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.104C>A	p.Pro35Gln	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.104C>A	p.Pro35Gln	missense	Exon 1 of 7	ENSP00000367797.4	P12755
SKI	ENST00000851187.1		c.104C>A	p.Pro35Gln	missense	Exon 1 of 7	ENSP00000521247.1
SKI	ENST00000704337.1		n.137+1346C>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1280408

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

632850

African (AFR)

AF:

0.00

AC:

AN:

26270

American (AMR)

AF:

0.00

AC:

AN:

26380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21054

East Asian (EAS)

AF:

0.00

AC:

AN:

26458

South Asian (SAS)

AF:

0.00

AC:

AN:

72180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1021288

Other (OTH)

AF:

0.00

AC:

AN:

51202

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Shprintzen-Goldberg syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Benign

0.96

DEOGEN2

Pathogenic

0.83

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.3

PhyloP100

6.8

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.91

MutPred

0.44

Gain of catalytic residue at P35 (P = 0.0047)

MVP

1.0

MPC

1.4

ClinPred

0.99

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.88

gMVP

0.81

Mutation Taster

=40/60

disease causing (ClinVar)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over