Genetic Variant NM_001128228.3:c.214_235delGGGGGCGCGGCGGGGGCGCGGC (chr9-137200476-AGCCGCGCCCCCGCCGCGCCCCC-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001128228.3(TPRN):c.214_235delGGGGGCGCGGCGGGGGCGCGGC(p.Gly72CysfsTer371) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 973,066 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G72G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TPRN
NM_001128228.3 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.33

Publications

0 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: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPRN	NM_001128228.3 link	c.214_235delGGGGGCGCGGCGGGGGCGCGGC	p.Gly72CysfsTer371	frameshift_variant	Exon 1 of 4	ENST00000409012.6	NP_001121700.2	Q4KMQ1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPRN	ENST00000409012.6 link	c.214_235delGGGGGCGCGGCGGGGGCGCGGC	p.Gly72CysfsTer371	frameshift_variant	Exon 1 of 4	1	NM_001128228.3	ENSP00000387100.4		Q4KMQ1-1
TPRN	ENST00000541945.1 link	n.90+3606_90+3627delGGGGGCGCGGCGGGGGCGCGGC		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000411

AC:

AN:

973066

Hom.:

AF XY:

0.00000427

AC XY:

AN XY:

468160

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18428

American (AMR)

AF:

0.00

AC:

AN:

6206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9166

East Asian (EAS)

AF:

0.00

AC:

AN:

10576

South Asian (SAS)

AF:

0.00

AC:

AN:

28246

European-Finnish (FIN)

AF:

0.000176

AC:

AN:

11386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2256

European-Non Finnish (NFE)

AF:

0.00000117

AC:

AN:

852112

Other (OTH)

AF:

0.0000288

AC:

AN:

34690

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.688

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

PhyloP100

3.3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over