9-137200476-AGCCGCGCCCCCGCCGCGCCCCC-AGCCGCGCCCCCGCCGCGCCCCCGCCGCGCCCCC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001128228.3(TPRN):c.225_235dupGGGGGCGCGGC(p.Leu79ArgfsTer375) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00005 in 1,118,928 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L79L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000055 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

TPRN
NM_001128228.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: -0.380

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 79
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TPRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 9-137200476-A-AGCCGCGCCCCC is Pathogenic according to our data. Variant chr9-137200476-A-AGCCGCGCCCCC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1180831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPRN	NM_001128228.3 link	c.225_235dupGGGGGCGCGGC	p.Leu79ArgfsTer375	frameshift_variant	Exon 1 of 4	ENST00000409012.6	NP_001121700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPRN	ENST00000409012.6 link	c.225_235dupGGGGGCGCGGC	p.Leu79ArgfsTer375	frameshift_variant	Exon 1 of 4	1	NM_001128228.3	ENSP00000387100.4
TPRN	ENST00000541945.1 link	n.90+3617_90+3627dupGGGGGCGCGGC		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes

AF:

0.0000549

AC:

AN:

145768

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000496

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000678

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000761

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000493

AC:

AN:

973068

Hom.:

Cov.:

AF XY:

0.0000513

AC XY:

AN XY:

468164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18428

American (AMR)

AF:

0.000161

AC:

AN:

6206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9166

East Asian (EAS)

AF:

0.0000945

AC:

AN:

10578

South Asian (SAS)

AF:

0.0000354

AC:

AN:

28248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

11386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2256

European-Non Finnish (NFE)

AF:

0.0000516

AC:

AN:

852110

Other (OTH)

AF:

0.0000288

AC:

AN:

34690

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000548

AC:

AN:

145860

Hom.:

Cov.:

AF XY:

0.0000282

AC XY:

AN XY:

71040

show subpopulations

African (AFR)

AF:

0.0000495

AC:

AN:

40442

American (AMR)

AF:

0.0000677

AC:

AN:

14770

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3384

East Asian (EAS)

AF:

0.00

AC:

AN:

4920

South Asian (SAS)

AF:

0.00

AC:

AN:

4758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.0000761

AC:

AN:

65668

Other (OTH)

AF:

0.00

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jan 18, 2023

GeneDx

Significance:Likely 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; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

May 16, 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.Leu79Argfs*375) 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 variant has not been reported in the literature in individuals affected with TPRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1180831). For these reasons, this variant has been classified as Pathogenic. -

Ear malformation

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.38

Mutation Taster

=22/178

disease causing (fs/PTC)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over