chr9-137192572-T-TTCCTCCTCCTCCTCCTCC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001128228.3(TPRN):c.1827_1844dupGGAGGAGGAGGAGGAGGA(p.Glu610_Glu615dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,608,424 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

TPRN
NM_001128228.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.164

Publications

3 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: Likely_benign. The variant received -1 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001128228.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPRN	NM_001128228.3 link	c.1827_1844dupGGAGGAGGAGGAGGAGGA	p.Glu610_Glu615dup	disruptive_inframe_insertion	Exon 2 of 4	ENST00000409012.6	NP_001121700.2	Q4KMQ1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TPRN	ENST00000409012.6 link	c.1827_1844dupGGAGGAGGAGGAGGAGGA	p.Glu610_Glu615dup	disruptive_inframe_insertion	Exon 2 of 4	1	NM_001128228.3	ENSP00000387100.4	Q4KMQ1-1
TPRN	ENST00000477345.1 link	n.2548_2565dupGGAGGAGGAGGAGGAGGA		non_coding_transcript_exon_variant	Exon 1 of 3	1
TPRN	ENST00000333046.8 link	c.1221_1238dupGGAGGAGGAGGAGGAGGA	p.Glu408_Glu413dup	disruptive_inframe_insertion	Exon 2 of 3	2		ENSP00000327617.4	H3BLU1
TPRN	ENST00000541945.1 link	n.62_79dupGGAGGAGGAGGAGGAGGA		downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000595

AC:

AN:

151158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000198

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.000482

GnomAD4 exome

AF:

0.0000247

AC:

AN:

1457154

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

724714

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000300

AC:

AN:

33354

American (AMR)

AF:

0.0000902

AC:

AN:

44344

Ashkenazi Jewish (ASJ)

AF:

0.0000768

AC:

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39552

South Asian (SAS)

AF:

0.00

AC:

AN:

85882

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52524

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1109484

Other (OTH)

AF:

0.0000997

AC:

AN:

60206

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.379

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:

0.0000595

AC:

AN:

151270

Hom.:

Cov.:

AF XY:

0.0000541

AC XY:

AN XY:

73908

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41254

American (AMR)

AF:

0.000197

AC:

AN:

15192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5068

South Asian (SAS)

AF:

0.00

AC:

AN:

4788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10456

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67754

Other (OTH)

AF:

0.000477

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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:

0.0000731

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with TPRN-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.1827_1844dup, results in the insertion of 6 amino acid(s) of the TPRN protein (p.Glu616_Glu621dup), but otherwise preserves the integrity of the reading frame. -

TPRN-related disorder

Uncertain:1

Jul 19, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TPRN c.1827_1844dup18 variant is predicted to result in an in-frame duplication (p.Glu616_Glu621dup). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.16

Mutation Taster

=75/25

polymorphism

(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