Genetic Variant TPRN:p.Gly76AlafsTer150 (chr9-137200476-AGCCGCGCCCCC-A) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001128228.3(TPRN):c.225_235delGGGGGCGCGGC(p.Gly76AlafsTer150) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,118,704 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

TPRN
NM_001128228.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 3.33

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: 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: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 9-137200476-AGCCGCGCCCCC-A is Pathogenic according to our data. Variant chr9-137200476-AGCCGCGCCCCC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.225_235delGGGGGCGCGGC	p.Gly76AlafsTer150	frameshift	Exon 1 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.225_235delGGGGGCGCGGC	p.Gly76AlafsTer150	frameshift	Exon 1 of 4	ENSP00000387100.4	Q4KMQ1-1
TPRN	ENST00000961754.1		c.225_235delGGGGGCGCGGC	p.Gly76AlafsTer150	frameshift	Exon 1 of 4	ENSP00000631813.1
TPRN	ENST00000541945.1	TSL:4	n.90+3617_90+3627delGGGGGCGCGGC		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000192

AC:

AN:

145768

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000203

Gnomad SAS

AF:

0.000420

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000259

Gnomad OTH

AF:

0.000494

GnomAD2 exomes

AF:

0.0000974

AC:

AN:

10264

AF XY:

0.000159

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00102

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000277

AC:

269

AN:

972844

Hom.:

AF XY:

0.000331

AC XY:

155

AN XY:

468018

show subpopulations

African (AFR)

AF:

0.000434

AC:

AN:

18428

American (AMR)

AF:

0.000970

AC:

AN:

6184

Ashkenazi Jewish (ASJ)

AF:

0.000218

AC:

AN:

9156

East Asian (EAS)

AF:

0.000567

AC:

AN:

10576

South Asian (SAS)

AF:

0.000887

AC:

AN:

28186

European-Finnish (FIN)

AF:

0.000439

AC:

AN:

11380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2256

European-Non Finnish (NFE)

AF:

0.000246

AC:

210

AN:

851994

Other (OTH)

AF:

0.000202

AC:

AN:

34684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000192

AC:

AN:

145860

Hom.:

Cov.:

AF XY:

0.000197

AC XY:

AN XY:

71040

show subpopulations

African (AFR)

AF:

0.000173

AC:

AN:

40442

American (AMR)

AF:

0.00

AC:

AN:

14770

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3384

East Asian (EAS)

AF:

0.000203

AC:

AN:

4920

South Asian (SAS)

AF:

0.000420

AC:

AN:

4758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.000259

AC:

AN:

65668

Other (OTH)

AF:

0.000489

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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:

0.0000540

Hom.:

Bravo

AF:

0.000170

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive nonsyndromic hearing loss 79 (5)

not provided (3)

Rare genetic deafness (1)

TPRN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.3

Mutation Taster

=7/193

disease causing (ClinVar)

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

9-137200476-AGCCGCGCCCCCGCCGCGCCCCC-AGCCGCGCCCCC

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