Genetic Variant TPRN:p.Arg636Gly (chr9-137192511-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001128228.3(TPRN):c.1906C>G(p.Arg636Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,796 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R636W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TPRN
NM_001128228.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.06

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPRN	NM_001128228.3 link	c.1906C>G	p.Arg636Gly	missense_variant	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.1906C>G	p.Arg636Gly	missense_variant	Exon 2 of 4	1	NM_001128228.3	ENSP00000387100.4	Q4KMQ1-1
TPRN	ENST00000477345.1 link	n.2627C>G		non_coding_transcript_exon_variant	Exon 1 of 3	1
TPRN	ENST00000333046.8 link	c.1300C>G	p.Arg434Gly	missense_variant	Exon 2 of 3	2		ENSP00000327617.4	H3BLU1
TPRN	ENST00000541945.1 link	n.*141C>G		downstream_gene_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453796

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722640

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33244

American (AMR)

AF:

0.00

AC:

AN:

43604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25982

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39256

South Asian (SAS)

AF:

0.00

AC:

AN:

85378

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51870

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108604

Other (OTH)

AF:

0.00

AC:

AN:

60118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

.;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.066

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.3

.;M

PhyloP100

3.1

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.23

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.19

T;D

Polyphen

1.0

.;D

Vest4

0.65

MutPred

0.29

.;Gain of sheet (P = 0.039);

MVP

0.10

ClinPred

0.98

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.55

Mutation Taster

=67/33

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over