NM_003036.4:c.94C>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_003036.4(SKI):​c.94C>G​(p.Leu32Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L32L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

SKI
NM_003036.4 missense

Scores

8
6
5

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.11

Publications

6 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_003036.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.791
PP5
Variant 1-2228860-C-G is Pathogenic according to our data. Variant chr1-2228860-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 37259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SKINM_003036.4 linkc.94C>G p.Leu32Val missense_variant Exon 1 of 7 ENST00000378536.5 NP_003027.1 P12755
SKIXM_005244775.4 linkc.94C>G p.Leu32Val missense_variant Exon 1 of 7 XP_005244832.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SKIENST00000378536.5 linkc.94C>G p.Leu32Val missense_variant Exon 1 of 7 1 NM_003036.4 ENSP00000367797.4 P12755
SKIENST00000704337.1 linkn.137+1336C>G intron_variant Intron 1 of 3

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Shprintzen-Goldberg syndrome Pathogenic:3
Aug 16, 2018
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 01, 2015
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

-
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

- -

Inborn genetic diseases Pathogenic:1
Dec 20, 2018
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.10
CADD
Benign
21
DANN
Benign
0.97
DEOGEN2
Pathogenic
0.81
D
Eigen
Benign
-0.22
Eigen_PC
Benign
-0.26
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.95
D
M_CAP
Pathogenic
0.84
D
MetaRNN
Pathogenic
0.79
D
MetaSVM
Uncertain
0.64
D
MutationAssessor
Benign
1.3
L
PhyloP100
3.1
PrimateAI
Pathogenic
0.93
D
PROVEAN
Uncertain
-2.4
N
REVEL
Uncertain
0.62
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.66
P
Vest4
0.76
MutPred
0.18
Gain of MoRF binding (P = 0.0945);
MVP
0.94
MPC
1.9
ClinPred
0.95
D
GERP RS
1.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.68
gMVP
0.74
Mutation Taster
=23/77
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387907304; hg19: chr1-2160299; API