rs387906221
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001128228.3(TPRN):c.225_235delGGGGGCGCGGC(p.Gly76fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,118,704 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00019 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00028 ( 1 hom. )
Consequence
TPRN
NM_001128228.3 frameshift
NM_001128228.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.33
Genes affected
TPRN (HGNC:26894): (taperin) This locus encodes a sensory epithelial protein. It was defined by linkage analysis in three Pakistani families to lie between D9S1818 (centromeric) and D9SH6 (telomeric). Mutations at this locus have been associated with autosomal recessive deafness. [provided by RefSeq, Oct 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-137200476-AGCCGCGCCCCC-A is Pathogenic according to our data. Variant chr9-137200476-AGCCGCGCCCCC-A is described in ClinVar as [Pathogenic]. Clinvar id is 137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137200476-AGCCGCGCCCCC-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TPRN | NM_001128228.3 | c.225_235delGGGGGCGCGGC | p.Gly76fs | frameshift_variant | 1/4 | ENST00000409012.6 | NP_001121700.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TPRN | ENST00000409012.6 | c.225_235delGGGGGCGCGGC | p.Gly76fs | frameshift_variant | 1/4 | 1 | NM_001128228.3 | ENSP00000387100.4 | ||
| TPRN | ENST00000541945.1 | n.90+3617_90+3627delGGGGGCGCGGC | intron_variant | 4 |
Frequencies
GnomAD3 genomes 0.000192 AC: 28AN: 145768Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000974 AC: 1AN: 10264Hom.: 0 AF XY: 0.000159 AC XY: 1AN XY: 6308
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GnomAD4 exome AF: 0.000277 AC: 269AN: 972844Hom.: 1 AF XY: 0.000331 AC XY: 155AN XY: 468018
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GnomAD4 genome 0.000192 AC: 28AN: 145860Hom.: 0 Cov.: 31 AF XY: 0.000197 AC XY: 14AN XY: 71040
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 79 Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Mar 01, 2023 | The frameshift c.225_235del(p.Gly76AlafsTer150) variant in TPRN gene has been observed in individual(s) with autosomal recessive nonsyndromic deafness (Bashir et. al., 2013; Rehman et. al., 2010). It has also been observed to segregate with disease in related individuals. This variant is also known as c.42_52del. The p.Gly76AlafsTer150 variant is novel (not in any individuals) in 1000 Genomes. 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 variant has been reported to the ClinVar database as Pathogenic by multiple submitters. This variant causes a frameshift starting with codon Glycine 76, changes this amino acid to Alanine residue, and creates a premature Stop codon at position 150 of the new reading frame, denoted p.Gly76AlafsTer150. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TPRN are known to be pathogenic (Rehman et. al., 2010). For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant in TPRN gene, the molecular diagnosis is not confirmed. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 30, 2022 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 12, 2010 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 29, 2022 | Variant summary: C9orf75 c.225_235del11 (p.Gly76AlafsX150) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00014 in 35206 control chromosomes (gnomAD). c.225_235del11 (also known as c.42_52del11) has been reported in the literature in multiple individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss 79 (e.g. Rehman_2010, Li_2010, Bashir_2013). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Comprehensive Medical Genetic Center, Shiraz University of Medical Sciences | - | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | This sequence change creates a premature translational stop signal (p.Gly76Alafs*150) in the TPRN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TPRN are known to be pathogenic (PMID: 20170898, 20170899). 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 premature translational stop signal has been observed in individual(s) with autosomal recessive nonsyndromic deafness (PMID: 20170898, 20170899, 23340767). It has also been observed to segregate with disease in related individuals. This variant is also known as c.42_52del. ClinVar contains an entry for this variant (Variation ID: 137). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 31, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20170898, 31980526, 23340767, 20170899) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
Rare genetic deafness Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 26, 2022 | The p.Gly76AlafsX150 variant in TPRN has been reported in altogether at least 7 individuals from a large consanguineous family with hearing loss from Morocco as well as in 6 affected members of 2 consanguineous families from Pakistan (Bashir 2013 PMID: 23340767, Rehman 2010 PMID: 20170899, Li 2010 PMID: 20170898, Hou 2020 PMID: 31980526) and in ClinVar (Variation ID 137). It has been identified in several subpopulations in gnomAD, including South Asian and European (2/4766 and 17/65678 chromosomes, respectively) (https://gnomad.broadinstitute.org/). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 76 and leads to a premature termination codon 150 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the TPRN gene is an established disease mechanism in autosomal recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PP1_Strong . - |
TPRN-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 06, 2024 | The TPRN c.225_235del11 variant is predicted to result in a frameshift and premature protein termination (p.Gly76Alafs*150). This variant was reported in the homozygous state in multiple individuals with hearing loss from two unrelated families (described as c.42_52del11; Li et al. 2010. PubMed ID: 20170898; Bashir et al. 2013. PubMed ID: 23340767). This variant is reported in 0.085% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Frameshift variants in TPRN are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at