rs775428246
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_138691.3(TMC1):c.236+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000237 in 1,604,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_138691.3 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152044Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000170 AC: 4AN: 235618Hom.: 0 AF XY: 0.0000315 AC XY: 4AN XY: 127136
GnomAD4 exome AF: 0.0000248 AC: 36AN: 1452776Hom.: 0 Cov.: 31 AF XY: 0.0000319 AC XY: 23AN XY: 722002
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152044Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74262
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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This sequence change affects a donor splice site in intron 7 of the TMC1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TMC1 are known to be pathogenic (PMID: 11850618, 22105175). 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. Disruption of this splice site has been observed in individuals with autosomal recessive deafness (PMID: 18616530, 23767834, 31028865, 31541171). ClinVar contains an entry for this variant (Variation ID: 504715). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 31541171, 18616530, 31028865, 21250555, 31589614, 33205915, 23767834, 27344577) -
Autosomal recessive nonsyndromic hearing loss 7 Pathogenic:3
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Autosomal dominant nonsyndromic hearing loss 36 Pathogenic:1
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Autosomal recessive nonsyndromic hearing loss 7;C1847626:Autosomal dominant nonsyndromic hearing loss 36 Pathogenic:1
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Hearing loss, autosomal recessive Pathogenic:1
The NM_138691.2:c.[236+1G>A] variant is a null variant in a gene where loss of function is a known mechanism of disease (PVS1), Extremely low frequency in gnomAD population databases (PM2), For recessive disorders, detected in trans with a pathogenic variant, or in a homozygous or compound heterozygous state in affected cases (PM3), Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1), reported in ClinVar in affected individuals (PP5), Here it was found in trans with c.1094G>A in two affected siblings, born from unaffected unrelated couple. -
Ear malformation Pathogenic:1
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Rare genetic deafness Pathogenic:1
The c.236+1G>A variant in TMC1 has been reported in 2 homozygous individuals wit h autosomal recessive nonsyndromic sensorineural hearing loss and segregated wit h hearing loss in 4 affected relatives from those 2 families (Hilgert 2008, Hild ebrand 2010). Another variant at the same position c.236+1G>C has also been repo rted as pathogenic in the literature (Yang 2013). This variant has been identifi ed in 1/42270 European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs775428246). Although this variant has been seen in the general population, its frequency is low enough to be consistent wi th a recessive carrier frequency. This variant occurs in the invariant region (+ /- 1/2) of the splice consensus sequence and is predicted to cause altered splic ing leading to an abnormal or absent protein. Loss of function of the TMC1 gene is an established disease mechanism in autosomal recessive nonsyndromic sensorin eural hearing loss. In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive nonsyndromic sensorineural hearing loss. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at