rs387906221

Positions:

• chr9-137200476-AGCCGCGCCCCC-A
• chr9-137200476-AGCCGCGCCCCC-AGCCGCGCCCCCGCCGCGCCCCC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001128228.3(TPRN):​c.225_235del​(p.Gly76AlafsTer150) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• 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]

ACMG classification

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_235del	p.Gly76AlafsTer150	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_235del	p.Gly76AlafsTer150	frameshift_variant	1/4	1	NM_001128228.3	ENSP00000387100	P1
TPRN	ENST00000541945.1	n.90+3617_90+3627del		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000192 AC: 28 AN: 145768 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.000420

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000259

Gnomad OTH AF: 0.000494

GnomAD3 exomes AF: 0.0000974 AC: 1 AN: 10264 Hom.: 0 AF XY: 0.000159 AC XY: 1 AN XY: 6308

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000277 AC: 269 AN: 972844 Hom.: 1 AF XY: 0.000331 AC XY: 155 AN XY: 468018

Gnomad4 AFR exome AF: 0.000434

Gnomad4 AMR exome AF: 0.000970

Gnomad4 ASJ exome AF: 0.000218

Gnomad4 EAS exome AF: 0.000567

Gnomad4 SAS exome AF: 0.000887

Gnomad4 FIN exome AF: 0.000439

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.000202

GnomAD4 genome AF: 0.000192 AC: 28 AN: 145860 Hom.: 0 Cov.: 31 AF XY: 0.000197 AC XY: 14 AN XY: 71040

Gnomad4 AFR AF: 0.000173

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000203

Gnomad4 SAS AF: 0.000420

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000259

Gnomad4 OTH AF: 0.000489

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.000170

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 79 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 30, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Comprehensive Medical Genetic Center, Shiraz University of Medical Sciences	-	- -
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	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	literature only	OMIM	Mar 12, 2010	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
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) -

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

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906221; hg19: chr9-140094928;