9-137192572-TTCCTCCTCCTCCTCCTCC-TTCCTCCTCCTCCTCCTCCTCCTCCTCCTCCTCC

Variant names:

• chr9-137192572-T-TTCCTCCTCCTCCTCC
• rs376810326
• NM_001128228.3:c.1830_1844dupGGAGGAGGAGGAGGA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001128228.3(TPRN):​c.1830_1844dupGGAGGAGGAGGAGGA​(p.Glu611_Glu615dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,158 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 INS_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.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TPRN NM_001128228.3 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.164
• Publications: 3 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_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001128228.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPRN	NM_001128228.3	c.1830_1844dupGGAGGAGGAGGAGGA	p.Glu611_Glu615dup	disruptive_inframe_insertion	Exon 2 of 4	ENST00000409012.6	NP_001121700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPRN	ENST00000409012.6	c.1830_1844dupGGAGGAGGAGGAGGA	p.Glu611_Glu615dup	disruptive_inframe_insertion	Exon 2 of 4	1	NM_001128228.3	ENSP00000387100.4
TPRN	ENST00000477345.1	n.2551_2565dupGGAGGAGGAGGAGGA		non_coding_transcript_exon_variant	Exon 1 of 3	1
TPRN	ENST00000333046.8	c.1224_1238dupGGAGGAGGAGGAGGA	p.Glu409_Glu413dup	disruptive_inframe_insertion	Exon 2 of 3	2		ENSP00000327617.4
TPRN	ENST00000541945.1	n.*65_*79dupGGAGGAGGAGGAGGA		downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000343 AC: 50 AN: 1457154 Hom.: 0 Cov.: 31 AF XY: 0.0000331 AC XY: 24 AN XY: 724716

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000300 AC: 1 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.00 AC: 0 AN: 85882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000442 AC: 49 AN: 1109482

Other (OTH) AF: 0.00 AC: 0 AN: 60206

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151158 Hom.: 0 Cov.: 33 AF XY: 0.0000271 AC XY: 2 AN XY: 73784

African (AFR) AF: 0.0000243 AC: 1 AN: 41136

American (AMR) AF: 0.00 AC: 0 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5080

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67762

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.0000365 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
Mutation Taster		=75/25	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs376810326; hg19: chr9-140087024;