chr3-46701415-C-T
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_147196.3(TMIE):c.-73C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000424 in 1,285,882 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 0 hom. )
Consequence
TMIE
NM_147196.3 5_prime_UTR
NM_147196.3 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.69
Genes affected
TMIE (HGNC:30800): (transmembrane inner ear) This gene encodes a transmembrane inner ear protein. Studies in mouse suggest that this gene is required for normal postnatal maturation of sensory hair cells in the cochlea, including correct development of stereocilia bundles. This gene is one of multiple genes responsible for recessive non-syndromic deafness (DFNB), also known as autosomal recessive nonsyndromic hearing loss (ARNSHL), the most common form of congenitally acquired inherited hearing impairment. [provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00219 (333/152310) while in subpopulation AFR AF= 0.00767 (319/41568). AF 95% confidence interval is 0.00698. There are 1 homozygotes in gnomad4. There are 169 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| TMIE | NM_147196.3 | c.-73C>T | 5_prime_UTR_variant | 1/4 | ENST00000643606.3 | ||
| TMIE | NM_001370524.1 | c.-66-4375C>T | intron_variant | ||||
| TMIE | NM_001370525.1 | c.-66-4375C>T | intron_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TMIE | ENST00000643606.3 | c.-73C>T | 5_prime_UTR_variant | 1/4 | NM_147196.3 | P1 | |||
| TMIE | ENST00000644830.1 | c.-66-4375C>T | intron_variant |
Frequencies
GnomAD3 genomes 0.00219 AC: 333AN: 152202Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.0000363 AC: 2AN: 55134Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 32574
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GnomAD4 exome AF: 0.000187 AC: 212AN: 1133572Hom.: 0 Cov.: 16 AF XY: 0.000164 AC XY: 92AN XY: 561526
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GnomAD4 genome 0.00219 AC: 333AN: 152310Hom.: 1 Cov.: 32 AF XY: 0.00227 AC XY: 169AN XY: 74462
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 6 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. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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