chr16-75555872-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_001077418.3(TMEM231):c.241C>T(p.Leu81Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000672 in 1,591,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001077418.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMEM231 | NM_001077418.3 | c.241C>T | p.Leu81Phe | missense_variant | Exon 2 of 7 | ENST00000258173.11 | NP_001070886.1 | |
TMEM231 | NM_001077416.2 | c.400C>T | p.Leu134Phe | missense_variant | Exon 1 of 6 | NP_001070884.2 | ||
TMEM231 | NR_074083.2 | n.284C>T | non_coding_transcript_exon_variant | Exon 2 of 7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TMEM231 | ENST00000258173.11 | c.241C>T | p.Leu81Phe | missense_variant | Exon 2 of 7 | 1 | NM_001077418.3 | ENSP00000258173.5 | ||
TMEM231 | ENST00000568377.5 | c.328C>T | p.Leu110Phe | missense_variant | Exon 1 of 6 | 1 | ENSP00000476267.1 | |||
TMEM231 | ENST00000565067.5 | c.241C>T | p.Leu81Phe | missense_variant | Exon 2 of 6 | 5 | ENSP00000457254.1 | |||
TMEM231 | ENST00000562410.5 | n.241C>T | non_coding_transcript_exon_variant | Exon 2 of 7 | 1 | ENSP00000454582.1 | ||||
TMEM231 | ENST00000570006.5 | n.241C>T | non_coding_transcript_exon_variant | Exon 2 of 7 | 5 | ENSP00000455520.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152240Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000188 AC: 4AN: 212802Hom.: 0 AF XY: 0.00000862 AC XY: 1AN XY: 116002
GnomAD4 exome AF: 0.0000716 AC: 103AN: 1438970Hom.: 0 Cov.: 30 AF XY: 0.0000729 AC XY: 52AN XY: 713190
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152240Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74380
ClinVar
Submissions by phenotype
Joubert syndrome 20;C3809352:Meckel syndrome, type 11 Pathogenic:1
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 134 of the TMEM231 protein (p.Leu134Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Joubert syndrome (PMID: 25869670). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.241C>T (p.Leu81Phe). ClinVar contains an entry for this variant (Variation ID: 445818). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects TMEM231 function (PMID: 25869670). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Ciliopathy Pathogenic:1
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Joubert syndrome 20 Pathogenic:1
A Homozygote Missense variant c.400C>T in Exon 1 of the TMEM231 gene that results in the amino acid substitution p.Leu134Phe was identified. The observed variant has a minor allele frequency of 0.00002 in gnomAD exomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as LikelyPathogenic (Variant ID: 445818). This missense variant has been observed in individual(s) with clinical features of Joubert syndrome. Experimental studies have shown that this missense change affects TMEM231 gene function (Roberson EC et al., 2015). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -
not provided Uncertain:1
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TMEM231-related disorder Uncertain:1
The TMEM231 c.400C>T variant is predicted to result in the amino acid substitution p.Leu134Phe. This variant was reported as c.241C>T in two related individuals with orofacial dysmorphism alongside another variant reported as c.373C>G (Braun et al. 2015. PubMed ID: 26489029; Roberson et al. 2015. PubMed ID: 25869670) and in one individual with a retinal disease (Sharon et al. 2019. PubMed ID: 31456290). This variant is reported in 0.0084% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may well be pathogenic, it is interpreted as uncertain at this time due to lack of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at