chr16-75556198-A-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_001077418.3(TMEM231):c.12T>A(p.Tyr4Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000747 in 1,473,338 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y4Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_001077418.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM231 | NM_001077418.3 | c.12T>A | p.Tyr4Ter | stop_gained | 1/7 | ENST00000258173.11 | |
TMEM231 | NM_001077416.2 | c.74T>A | p.Met25Lys | missense_variant | 1/6 | ||
TMEM231 | NR_074083.2 | n.55T>A | non_coding_transcript_exon_variant | 1/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM231 | ENST00000258173.11 | c.12T>A | p.Tyr4Ter | stop_gained | 1/7 | 1 | NM_001077418.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152252Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000100 AC: 1AN: 99892Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 55562
GnomAD4 exome AF: 0.00000681 AC: 9AN: 1321086Hom.: 0 Cov.: 30 AF XY: 0.00000310 AC XY: 2AN XY: 645198
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74382
ClinVar
Submissions by phenotype
Joubert syndrome 20;C3809352:Meckel syndrome, type 11 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 08, 2023 | ClinVar contains an entry for this variant (Variation ID: 39821). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 25 of the TMEM231 protein (p.Met25Lys). 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 Joubert syndrome (PMID: 23012439). 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.12T>A, p.Tyr4*. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. - |
Joubert syndrome 20 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2012 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 29, 2021 | Variant summary: TMEM231 c.74T>A (p.Met25Lys) results in a non-conservative amino acid change in the longest isoform (NM_001077416.2) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. However, the variant results in a nonsense alteration, c.12T>A (p.Tyr4X), in the canonical isoform of TMEM231 (NM_001077418.1; Srour_2012), in addition, it abolishes the translation initiation methionine (c.2T>A (p.Met1?)) in another isoform of TMEM231 (NM_001077416.1). The variant allele was found at a frequency of 1.5e-05 in 131278 control chromosomes (gnomAD). The variant, described as c.12T>A (p.Tyr4X) has been reported in the literature in three compound heterozygous Canadian-French individuals from 2 families, who were affected with Joubert Syndrome and Related Disorders (Srour_2012, Srour_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at