rs397514609
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2
The ENST00000568377.5(TMEM231):āc.2T>Cā(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000122 in 1,473,338 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 Uncertain significance (ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 33)
Exomes š: 0.000011 ( 0 hom. )
Consequence
TMEM231
ENST00000568377.5 start_lost
ENST00000568377.5 start_lost
Scores
1
1
10
Clinical Significance
Conservation
PhyloP100: 0.885
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 Pathogenic. Variant got 12 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in ENST00000568377.5 (TMEM231) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 39821
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM231 | NM_001077418.3 | c.12T>C | p.Tyr4= | synonymous_variant | 1/7 | ENST00000258173.11 | |
TMEM231 | NM_001077416.2 | c.74T>C | p.Met25Thr | missense_variant | 1/6 | ||
TMEM231 | NR_074083.2 | n.55T>C | non_coding_transcript_exon_variant | 1/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM231 | ENST00000258173.11 | c.12T>C | p.Tyr4= | synonymous_variant | 1/7 | 1 | NM_001077418.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152252Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000100 AC: 1AN: 99892Hom.: 0 AF XY: 0.0000180 AC XY: 1AN XY: 55562
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GnomAD4 exome AF: 0.0000114 AC: 15AN: 1321086Hom.: 0 Cov.: 30 AF XY: 0.0000186 AC XY: 12AN XY: 645198
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74382
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Joubert syndrome 20;C3809352:Meckel syndrome, type 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 21, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 25 of the TMEM231 protein (p.Met25Thr). 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 variant has not been reported in the literature in individuals affected with TMEM231-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Met25 amino acid residue in TMEM231. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23012439). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
Sift4G
Pathogenic
D
Vest4
MVP
ClinPred
T
GERP RS
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