Genetic Variant NM_001128228.3:c.227_237dupGGGCGCGGCTG (chr9-137200474-G-GCAGCCGCGCCC) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_001128228.3(TPRN):c.227_237dupGGGCGCGGCTG(p.Leu80GlyfsTer374) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L79L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TPRN
NM_001128228.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: -0.0490

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: Labcorp Genetics (formerly Invitae), PanelApp Australia, 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

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

PP5

Variant 9-137200474-G-GCAGCCGCGCCC is Pathogenic according to our data. Variant chr9-137200474-G-GCAGCCGCGCCC is described in ClinVar as Pathogenic. ClinVar VariationId is 136.Status of the report is no_assertion_criteria_provided, 0 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.227_237dupGGGCGCGGCTG	p.Leu80GlyfsTer374	frameshift	Exon 1 of 4	NP_001121700.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TPRN	ENST00000409012.6	TSL:1 MANE Select	c.227_237dupGGGCGCGGCTG	p.Leu80GlyfsTer374	frameshift	Exon 1 of 4	ENSP00000387100.4
TPRN	ENST00000961754.1		c.227_237dupGGGCGCGGCTG	p.Leu80GlyfsTer374	frameshift	Exon 1 of 4	ENSP00000631813.1
TPRN	ENST00000541945.1	TSL:4	n.90+3619_90+3629dupGGGCGCGGCTG		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

974548

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

469186

African (AFR)

AF:

0.00

AC:

AN:

18414

American (AMR)

AF:

0.00

AC:

AN:

6254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9216

East Asian (EAS)

AF:

0.00

AC:

AN:

10488

South Asian (SAS)

AF:

0.00

AC:

AN:

29040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

11450

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2252

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

852670

Other (OTH)

AF:

0.00

AC:

AN:

34764

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive nonsyndromic hearing loss 79 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.049

Mutation Taster

=14/186

disease causing (ClinVar)

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over