9-137192179-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001128228.3(TPRN):​c.2074-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TPRN
NM_001128228.3 splice_region, splice_polypyrimidine_tract, intron

Scores

1
14
Splicing: ADA: 0.0005680
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.363
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.105929494).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TPRNNM_001128228.3 linkuse as main transcriptc.2074-5T>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000409012.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TPRNENST00000409012.6 linkuse as main transcriptc.2074-5T>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_001128228.3 P1Q4KMQ1-1
TPRNENST00000477345.1 linkuse as main transcriptn.2795-5T>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant 1
TPRNENST00000333046.8 linkuse as main transcriptc.1547T>C p.Phe516Ser missense_variant 3/32

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250802
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135814
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461210
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726922
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 01, 2019The c.2074-5T>C variant in TPRN has not been previously reported in individuals with hearing loss but has been identified in 0.0008% (1/113236) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is in the 3' splice region. Computational tools do not predict a splicing impact, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
5.1
DANN
Benign
0.67
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.68
FATHMM_MKL
Benign
0.0087
N
LIST_S2
Benign
0.20
T
M_CAP
Benign
0.0013
T
MetaRNN
Benign
0.11
T
MetaSVM
Benign
-0.99
T
MutationTaster
Benign
1.0
D;N
PROVEAN
Benign
0.28
N
REVEL
Benign
0.0090
Sift
Uncertain
0.023
D
Sift4G
Benign
0.19
T
MutPred
0.40
Gain of disorder (P = 3e-04);
MVP
0.067
ClinPred
0.020
T
GERP RS
-0.44
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00057
dbscSNV1_RF
Benign
0.044
SpliceAI score (max)
0.080
Details are displayed if max score is > 0.2

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.

Other links and lift over

dbSNP: rs1564383004; hg19: chr9-140086631; API