Variant 9-137200476-AGCCGCGCCCCC-AGCCGCGCCCCCGCCGCGCCCCC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001128228.3(TPRN):c.235_236insGGGGGCGCGGC(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. Variant has been reported in ClinVar as Likely pathogenic (★★). 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

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-A-AGCCGCGCCCCC is Pathogenic according to our data. Variant chr9-137200476-A-AGCCGCGCCCCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1180831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPRN	NM_001128228.3 linkuse as main transcript	c.235_236insGGGGGCGCGGC	p.Leu79ArgfsTer375	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 linkuse as main transcript	c.235_236insGGGGGCGCGGC	p.Leu79ArgfsTer375	frameshift_variant	1/4	1	NM_001128228.3	ENSP00000387100	P1	Q4KMQ1-1
TPRN	ENST00000541945.1 linkuse as main transcript	n.90+3627_90+3628insGGGGGCGCGGC		intron_variant, non_coding_transcript_variant		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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000161

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000945

Gnomad4 SAS exome

AF:

0.0000354

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000516

Gnomad4 OTH exome

AF:

0.0000288

GnomAD4 genome

AF:

0.0000548

AC:

AN:

145860

Hom.:

Cov.:

AF XY:

0.0000282

AC XY:

AN XY:

71040

show subpopulations

Gnomad4 AFR

AF:

0.0000495

Gnomad4 AMR

AF:

0.0000677

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000761

Gnomad4 OTH

AF:

0.00

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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 02, 2023	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. For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with TPRN-related conditions. 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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2023	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 -

Ear malformation

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

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