rs557289756

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The ENST00000378536.5(SKI):​c.1205G>A​(p.Arg402Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,611,980 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R402G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 1 hom. )

Consequence

SKI
ENST00000378536.5 missense

Scores

5
9
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 8.59
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6
Variant 1-2303394-G-A is Benign according to our data. Variant chr1-2303394-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409972.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS2
High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SKINM_003036.4 linkuse as main transcriptc.1205G>A p.Arg402Gln missense_variant 3/7 ENST00000378536.5 NP_003027.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SKIENST00000378536.5 linkuse as main transcriptc.1205G>A p.Arg402Gln missense_variant 3/71 NM_003036.4 ENSP00000367797 P1
SKIENST00000704337.1 linkuse as main transcriptn.373G>A non_coding_transcript_exon_variant 3/4
SKIENST00000478223.2 linkuse as main transcript downstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152126
Hom.:
0
Cov.:
32
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:
0.000193
Gnomad SAS
AF:
0.000415
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250350
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135482
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 SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000158
AC:
23
AN:
1459736
Hom.:
1
Cov.:
32
AF XY:
0.0000207
AC XY:
15
AN XY:
726260
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.000104
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152244
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74444
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000416
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000286
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000247
AC:
3
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Shprintzen-Goldberg syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityOct 27, 2023- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 04, 2024- -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 12, 2024The p.R402Q variant (also known as c.1205G>A), located in coding exon 3 of the SKI gene, results from a G to A substitution at nucleotide position 1205. The arginine at codon 402 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Uncertain
0.091
D
BayesDel_noAF
Uncertain
0.070
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.44
T
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
D
M_CAP
Pathogenic
0.66
D
MetaRNN
Uncertain
0.71
D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Uncertain
2.3
M
MutationTaster
Benign
0.98
D
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-1.2
N
REVEL
Pathogenic
0.68
Sift
Benign
0.047
D
Sift4G
Benign
0.18
T
Polyphen
1.0
D
Vest4
0.69
MutPred
0.44
Loss of loop (P = 0.0374);
MVP
0.82
MPC
0.80
ClinPred
0.90
D
GERP RS
4.0
Varity_R
0.13
gMVP
0.48

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: rs557289756; hg19: chr1-2234833; COSMIC: COSV66013275; COSMIC: COSV66013275; API