rs769707569

Variant names:

• chr9-137192684-ATCT-A
• rs769707569
• NM_001128228.3:c.1730_1732delAGA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM4_Supporting BS1_Supporting

The NM_001128228.3(TPRN):​c.1730_1732delAGA​(p.Lys577del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000372 in 1,613,484 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: TPRN NM_001128228.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.36
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001128228.3. Strenght limited to Supporting due to length of the change: 1aa.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000158 (24/152034) while in subpopulation AMR AF = 0.00157 (24/15272). AF 95% confidence interval is 0.00108. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPRN	NM_001128228.3	c.1730_1732delAGA	p.Lys577del	disruptive_inframe_deletion	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.1730_1732delAGA	p.Lys577del	disruptive_inframe_deletion	Exon 2 of 4	1	NM_001128228.3	ENSP00000387100.4
TPRN	ENST00000477345.1	n.2451_2453delAGA		non_coding_transcript_exon_variant	Exon 1 of 3	1
TPRN	ENST00000333046.8	c.1124_1126delAGA	p.Lys375del	disruptive_inframe_deletion	Exon 2 of 3	2		ENSP00000327617.4
TPRN	ENST00000541945.1	n.95_97delAGA		non_coding_transcript_exon_variant	Exon 2 of 2	4

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152034 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000846 AC: 21 AN: 248308 AF XY: 0.0000817

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

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: 0.0000246 AC: 36 AN: 1461450 Hom.: 0 AF XY: 0.0000248 AC XY: 18 AN XY: 727020

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000649 AC: 29 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111952

Other (OTH) AF: 0.0000662 AC: 4 AN: 60386

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152034 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74238

African (AFR) AF: 0.00 AC: 0 AN: 41384

American (AMR) AF: 0.00157 AC: 24 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000215

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 27, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys577del variant in TPRN has been previously reported in one individual w ith hearing loss by our laboratory. It has been identified in 21/34412 of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org/; dbSNP rs769707569). This variant is a deletion of a single amino aci d at position 577 and is not predicted to alter the protein reading frame. It is unclear if this deletion would impact the normal function of the protein. In su mmary, the clinical significance of the p.Lys577del variant is uncertain. ACMG/A MP Criteria applied: PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs769707569; hg19: chr9-140087136;