Genetic Variant TPRN:p.Gly76AlafsTer150 (chr9-137200476-AGCCGCGCCCCC-A) – ACMG Classification: Pathogenic (18 pts)

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.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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 3.33

Variant links:

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]

TPRN links:

Genome browser will be placed here

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 rank	MANE	Protein	UniProt
TPRN	NM_001128228.3 link	c.225_235delGGGGGCGCGGC	p.Gly76AlafsTer150	frameshift_variant	Exon 1 of 4	ENST00000409012.6	NP_001121700.2	Q4KMQ1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPRN	ENST00000409012.6 link	c.225_235delGGGGGCGCGGC	p.Gly76AlafsTer150	frameshift_variant	Exon 1 of 4	1	NM_001128228.3	ENSP00000387100.4		Q4KMQ1-1
TPRN	ENST00000541945.1 link	n.90+3617_90+3627delGGGGGCGCGGC		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes

AF:

0.000192

AC:

AN:

145768

Hom.:

Cov.:

show subpopulations

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:

AN:

10264

Hom.:

AF XY:

0.000159

AC XY:

AN XY:

6308

show subpopulations

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.:

AF XY:

0.000331

AC XY:

155

AN XY:

468018

show subpopulations

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:

AN:

145860

Hom.:

Cov.:

AF XY:

0.000197

AC XY:

AN XY:

71040

show subpopulations

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.:

Bravo

AF:

0.000170

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

Apr 29, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 01, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 12, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Comprehensive Medical Genetic Center, Shiraz University of Medical Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 30, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 31, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rare genetic deafness

Pathogenic:1

Aug 26, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over