NM_001128228.3:c.2057C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_001128228.3(TPRN):​c.2057C>T​(p.Pro686Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,612,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

TPRN
NM_001128228.3 missense

Scores

2
17

Clinical Significance

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

Conservation

PhyloP100: 0.704

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08209035).
BP6
Variant 9-137192275-G-A is Benign according to our data. Variant chr9-137192275-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165576.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TPRNNM_001128228.3 linkc.2057C>T p.Pro686Leu missense_variant Exon 3 of 4 ENST00000409012.6 NP_001121700.2 Q4KMQ1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TPRNENST00000409012.6 linkc.2057C>T p.Pro686Leu missense_variant Exon 3 of 4 1 NM_001128228.3 ENSP00000387100.4 Q4KMQ1-1
TPRNENST00000477345.1 linkn.2778C>T non_coding_transcript_exon_variant Exon 2 of 3 1
TPRNENST00000333046.8 linkc.1451C>T p.Pro484Leu missense_variant Exon 3 of 3 2 ENSP00000327617.4 H3BLU1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000241
AC:
6
AN:
249356
AF XY:
0.0000295
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000609
AC:
89
AN:
1460682
Hom.:
0
Cov.:
31
AF XY:
0.0000482
AC XY:
35
AN XY:
726656
show subpopulations
African (AFR)
AF:
0.0000896
AC:
3
AN:
33480
American (AMR)
AF:
0.0000671
AC:
3
AN:
44714
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26124
East Asian (EAS)
AF:
0.0000504
AC:
2
AN:
39700
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86250
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52274
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000674
AC:
75
AN:
1111992
Other (OTH)
AF:
0.0000662
AC:
4
AN:
60380
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.487
Heterozygous variant carriers
0
6
12
18
24
30
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<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:
0.00000657
AC:
1
AN:
152216
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74364
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41466
American (AMR)
AF:
0.0000654
AC:
1
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10632
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68022
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 79 Uncertain:1
Nov 16, 2015
Division of Human Genetics, Children's Hospital of Philadelphia
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:research

- -

not provided Uncertain:1
May 22, 2023
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Benign:1
Oct 06, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

p.Pro686Leu in exon 3 of TPRN: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, at least five mammalian species have a leucine (Leu) at this position despit e high nearby amino acid conservation. In addition, computational prediction too ls do not suggest a high likelihood of impact to the protein. It has been identi fied in 2/16500 South Asian chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
13
DANN
Uncertain
0.98
DEOGEN2
Benign
0.0071
.;T
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.79
FATHMM_MKL
Benign
0.080
N
LIST_S2
Benign
0.51
T;T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.082
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
.;L
PhyloP100
0.70
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-2.1
N;D
REVEL
Benign
0.055
Sift
Uncertain
0.0020
D;D
Sift4G
Benign
0.14
T;T
Polyphen
0.035
.;B
Vest4
0.15
MutPred
0.26
.;Loss of glycosylation at P686 (P = 0.0156);
MVP
0.15
ClinPred
0.094
T
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.047
gMVP
0.20
Mutation Taster
=95/5
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs727503520; hg19: chr9-140086727; API