rs137853186
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_001393500.2(TOMT):c.214T>C(p.Trp72Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000729 in 1,371,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 7.3e-7 ( 0 hom. )
Consequence
TOMT
NM_001393500.2 missense
NM_001393500.2 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 7.08
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 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.854
PP5
?
Variant 11-72106165-T-C is Pathogenic according to our data. Variant chr11-72106165-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 544.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72106165-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TOMT | NM_001393500.2 | c.214T>C | p.Trp72Arg | missense_variant | 1/3 | ENST00000541899.3 | |
LRTOMT | NM_001145309.4 | c.313T>C | p.Trp105Arg | missense_variant | 7/9 | ||
LRTOMT | NM_001145308.5 | c.313T>C | p.Trp105Arg | missense_variant | 5/7 | ||
LRTOMT | NM_001145310.4 | c.193T>C | p.Trp65Arg | missense_variant | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TOMT | ENST00000541899.3 | c.214T>C | p.Trp72Arg | missense_variant | 1/3 | 5 | NM_001393500.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 7.29e-7 AC: 1AN: 1371368Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 672444
GnomAD4 exome
AF:
AC:
1
AN:
1371368
Hom.:
Cov.:
30
AF XY:
AC XY:
0
AN XY:
672444
Gnomad4 AFR exome
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Gnomad4 EAS exome
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Gnomad4 SAS exome
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Gnomad4 FIN exome
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Gnomad4 OTH exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 63 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2008 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;.;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.
Sift4G
Pathogenic
D;D;.
Polyphen
D;D;.
Vest4
MutPred
Gain of disorder (P = 0.0059);Gain of disorder (P = 0.0059);.;
MVP
MPC
0.51
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at