rs387907304

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L32P) has been classified as Likely pathogenic.

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
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 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, 6 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 chrnull-null-null-null is described in UniProt as null.
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. Variant chr1-2228860-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SKINM_003036.4 linkuse as main transcriptc.94C>G p.Leu32Val missense_variant 1/7 ENST00000378536.5
SKIXM_005244775.4 linkuse as main transcriptc.94C>G p.Leu32Val missense_variant 1/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SKIENST00000378536.5 linkuse as main transcriptc.94C>G p.Leu32Val missense_variant 1/71 NM_003036.4 P1
SKIENST00000704337.1 linkuse as main transcriptn.137+1336C>G intron_variant, non_coding_transcript_variant

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
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneAug 16, 2018- -
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 2015- -
Pathogenic, criteria provided, single submitterresearchBaylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine-- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsDec 20, 2018- -

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
MutationTaster
Benign
1.0
D
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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs387907304; hg19: chr1-2160299; API