chr16-75542598-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_001077418.3(TMEM231):c.664+4A>G variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.0000483 in 1,613,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000048 ( 0 hom. )
Consequence
TMEM231
NM_001077418.3 splice_donor_region, intron
NM_001077418.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9819
1
1
Clinical Significance
Conservation
PhyloP100: 3.93
Genes affected
TMEM231 (HGNC:37234): (transmembrane protein 231) This gene encodes a transmembrane protein, which is a component of the B9 complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. Mutations in this gene cause Joubert syndrome (JBTS). Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
PP5
Variant 16-75542598-T-C is Pathogenic according to our data. Variant chr16-75542598-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437009.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM231 | NM_001077418.3 | c.664+4A>G | splice_donor_region_variant, intron_variant | ENST00000258173.11 | |||
TMEM231 | NM_001077416.2 | c.823+4A>G | splice_donor_region_variant, intron_variant | ||||
TMEM231 | NR_074083.2 | n.830+4A>G | splice_donor_region_variant, intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM231 | ENST00000258173.11 | c.664+4A>G | splice_donor_region_variant, intron_variant | 1 | NM_001077418.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152104Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000682 AC: 17AN: 249240Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135218
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GnomAD4 exome AF: 0.0000479 AC: 70AN: 1461396Hom.: 0 Cov.: 30 AF XY: 0.0000468 AC XY: 34AN XY: 727006
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GnomAD4 genome AF: 0.0000526 AC: 8AN: 152104Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74318
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Meckel syndrome, type 11 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 08, 2016 | - - |
Joubert syndrome 20;C3809352:Meckel syndrome, type 11 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change falls in intron 4 of the TMEM231 gene. It does not directly change the encoded amino acid sequence of the TMEM231 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs760426025, gnomAD 0.02%). This variant has been observed in individual(s) with Meckel syndrome (PMID: 25869670). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 437009). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in altered splicing and introduces a premature termination codon (PMID: 25869670). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 24, 2022 | - - |
Joubert syndrome and related disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 15, 2023 | Variant summary: TMEM231 c.823+4A>G, also referred to as c.664+4A>G, alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' donor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing and results in a frameshift leading to a premature truncation that is expected to undergo nonsense mediated decay (Roberson_2015). The variant allele was found at a frequency of 6.8e-05 in 249240 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TMEM231 causing Joubert Syndrome And Related Disorders (6.8e-05 vs 0.0004), allowing no conclusion about variant significance. c.823+4A>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Meckel Syndrome from several different families (Roberson_2015). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 25869670). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Joubert syndrome 20 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -43
DS_DL_spliceai
Position offset: 4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at