chr9-137192137-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001128228.3(TPRN):c.2111G>A(p.Arg704His) variant causes a missense change. The variant allele was found at a frequency of 0.0000868 in 1,613,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R704C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

TPRN
NM_001128228.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.86

Publications

2 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057493925).

BP6

Variant 9-137192137-C-T is Benign according to our data. Variant chr9-137192137-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1195124.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000691 (101/1461254) while in subpopulation AFR AF = 0.00137 (46/33480). AF 95% confidence interval is 0.00106. There are 0 homozygotes in GnomAdExome4. There are 43 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128228.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPRN	NM_001128228.3	MANE Select	c.2111G>A	p.Arg704His	missense	Exon 4 of 4	NP_001121700.2	Q4KMQ1-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPRN	ENST00000409012.6	TSL:1 MANE Select	c.2111G>A	p.Arg704His	missense	Exon 4 of 4	ENSP00000387100.4	Q4KMQ1-1
TPRN	ENST00000477345.1	TSL:1	n.2832G>A		non_coding_transcript_exon	Exon 3 of 3
TPRN	ENST00000961754.1		c.2045G>A	p.Arg682His	missense	Exon 4 of 4	ENSP00000631813.1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000918

AC:

AN:

250488

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.00118

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000691

AC:

101

AN:

1461254

Hom.:

Cov.:

AF XY:

0.0000592

AC XY:

AN XY:

726948

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52826

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000459

AC:

AN:

1111990

Other (OTH)

AF:

0.0000166

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.000256

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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:

0.000583

Hom.:

Bravo

AF:

0.000431

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.021

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.64

M_CAP

Benign

0.051

MetaRNN

Benign

0.057

MetaSVM

Benign

-0.48

MutationAssessor

Benign

2.0

PhyloP100

4.9

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.6

REVEL

Benign

0.15

Sift

Uncertain

0.0030

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.32

MVP

0.030

ClinPred

0.12

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.36

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over