rs387906220

Variant names:

• chr9-137200474-G-GCAGCCGCGCCC
• rs387906220
• NM_001128228.3:c.227_237dupGGGCGCGGCTG

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.0490
• Publications: 2 publications found

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

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPRN	NM_001128228.3	c.227_237dupGGGCGCGGCTG	p.Leu80GlyfsTer374	frameshift_variant	Exon 1 of 4	ENST00000409012.6	NP_001121700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPRN	ENST00000409012.6	c.227_237dupGGGCGCGGCTG	p.Leu80GlyfsTer374	frameshift_variant	Exon 1 of 4	1	NM_001128228.3	ENSP00000387100.4
TPRN	ENST00000541945.1	n.90+3619_90+3629dupGGGCGCGGCTG		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 974548 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 469186

African (AFR) AF: 0.00 AC: 0 AN: 18414

American (AMR) AF: 0.00 AC: 0 AN: 6254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9216

East Asian (EAS) AF: 0.00 AC: 0 AN: 10488

South Asian (SAS) AF: 0.00 AC: 0 AN: 29040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2252

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 852670

Other (OTH) AF: 0.00 AC: 0 AN: 34764

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 79 Pathogenic:1

Mar 12, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.049
Mutation Taster		=14/186	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs387906220; hg19: chr9-140094926;