rs886048633
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001393500.2(TOMT):āc.681T>Gā(p.Cys227Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000774 in 1,550,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 32)
Exomes š: 0.0000057 ( 0 hom. )
Consequence
TOMT
NM_001393500.2 missense
NM_001393500.2 missense
Scores
2
11
6
Clinical Significance
Conservation
PhyloP100: 0.444
Genes affected
TOMT (HGNC:55527): (transmembrane O-methyltransferase) This gene encodes a catechol-O-methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to a hydroxyl group of catechols and is essential for auditory and vestibular function. Mutations in this gene have been associated with nonsyndromic deafness. Readthrough transcription is observed across this gene and the adjacent leucine-rich repeat containing 51 gene. A third locus (GeneID:220074) is defined to represent the readthrough transcripts. [provided by RefSeq, Feb 2021]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TOMT | NM_001393500.2 | c.681T>G | p.Cys227Trp | missense_variant | 3/3 | ENST00000541899.3 | |
LRTOMT | NM_001145309.4 | c.780T>G | p.Cys260Trp | missense_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TOMT | ENST00000541899.3 | c.681T>G | p.Cys227Trp | missense_variant | 3/3 | 5 | NM_001393500.2 | P1 | |
ANAPC15 | ENST00000502597.2 | c.64-1224A>C | intron_variant | 1 | |||||
ANAPC15 | ENST00000543050.5 | c.319-1224A>C | intron_variant | 3 | |||||
ANAPC15 | ENST00000538117.5 | c.*145A>C | 3_prime_UTR_variant, NMD_transcript_variant | 6/6 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152222Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000195 AC: 3AN: 154162Hom.: 0 AF XY: 0.0000122 AC XY: 1AN XY: 81902
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GnomAD4 exome AF: 0.00000572 AC: 8AN: 1398412Hom.: 0 Cov.: 32 AF XY: 0.00000435 AC XY: 3AN XY: 689778
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74370
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 02, 2016 | The p.Cys260Trp variant in LRTOMT has not been previously reported in individual s with hearing loss or in large population studies. Computational prediction too ls and conservation analyses do not provide strong support for or against an imp act to the protein. In summary, the clinical significance of the p.Cys260Trp var iant is uncertain. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 10, 2022 | The c.780T>G (p.C260W) alteration is located in exon 7 (coding exon 5) of the LRTOMT gene. This alteration results from a T to G substitution at nucleotide position 780, causing the cysteine (C) at amino acid position 260 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Autosomal recessive nonsyndromic hearing loss 63 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 12, 2022 | This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 260 of the LRTOMT protein (p.Cys260Trp). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with LRTOMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 305999). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.
REVEL
Uncertain
Sift
Uncertain
D;D;.
Sift4G
Uncertain
D;D;.
Polyphen
D;D;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0123);Gain of MoRF binding (P = 0.0123);.;
MVP
MPC
0.44
ClinPred
D
GERP RS
Varity_R
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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