rs534237033
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014639.4(SKIC3):c.2808G>A(p.Trp936Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000297 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
SKIC3
NM_014639.4 stop_gained
NM_014639.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 5.52
Genes affected
SKIC3 (HGNC:23639): (SKI3 subunit of superkiller complex) This gene encodes a protein with twenty tetratricopeptide (TPR) repeats. Tetratricopeptide repeat containing motifs are found in a variety of proteins and may mediate protein-protein interactions and chaperone activity. Mutations in this gene are associated with trichohepatoenteric syndrome. [provided by RefSeq, Jul 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-95512589-C-T is Pathogenic according to our data. Variant chr5-95512589-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 196135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-95512589-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| SKIC3 | NM_014639.4 | c.2808G>A | p.Trp936Ter | stop_gained | 28/43 | ENST00000358746.7 | |
| SKIC3 | XM_047417937.1 | c.2808G>A | p.Trp936Ter | stop_gained | 28/43 | ||
| SKIC3 | XM_047417938.1 | c.2778+982G>A | intron_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SKIC3 | ENST00000358746.7 | c.2808G>A | p.Trp936Ter | stop_gained | 28/43 | 1 | NM_014639.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152020Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251276Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135804
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GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461700Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28AN XY: 727148
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152138Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74360
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change creates a premature translational stop signal (p.Trp936*) in the TTC37 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TTC37 are known to be pathogenic (PMID: 20176027, 21120949). This variant is present in population databases (rs534237033, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with trichohepatoenteric syndrome (PMID: 20176027, 23326254). ClinVar contains an entry for this variant (Variation ID: 196135). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 14, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 07, 2020 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23326254, 20176027) - |
Trichohepatoenteric syndrome 1 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2010 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A
Vest4
0.47
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at