Genetic Variant TPRN:p.Glu614_Glu615dup (chr9-137192572-T-TTCCTCC) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP3BP6_Moderate

The NM_001128228.3(TPRN):c.1839_1844dupGGAGGA(p.Glu614_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 0.000122 in 1,608,426 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TPRN
NM_001128228.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.164

Publications

3 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_benign. The variant received -3 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001128228.3

BP6

Variant 9-137192572-T-TTCCTCC is Benign according to our data. Variant chr9-137192572-T-TTCCTCC is described in ClinVar as Likely_benign. ClinVar VariationId is 228022.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPRN	NM_001128228.3 link	c.1839_1844dupGGAGGA	p.Glu614_Glu615dup	disruptive_inframe_insertion	Exon 2 of 4	ENST00000409012.6	NP_001121700.2	Q4KMQ1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TPRN	ENST00000409012.6 link	c.1839_1844dupGGAGGA	p.Glu614_Glu615dup	disruptive_inframe_insertion	Exon 2 of 4	1	NM_001128228.3	ENSP00000387100.4	Q4KMQ1-1
TPRN	ENST00000477345.1 link	n.2560_2565dupGGAGGA		non_coding_transcript_exon_variant	Exon 1 of 3	1
TPRN	ENST00000333046.8 link	c.1233_1238dupGGAGGA	p.Glu412_Glu413dup	disruptive_inframe_insertion	Exon 2 of 3	2		ENSP00000327617.4	H3BLU1
TPRN	ENST00000541945.1 link	n.74_79dupGGAGGA		downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000152

AC:

AN:

151158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000170

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000394

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000956

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000192

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000152

AC:

AN:

209928

AF XY:

0.000167

show subpopulations

Gnomad AFR exome

AF:

0.000148

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0000545

Gnomad NFE exome

AF:

0.000239

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000119

AC:

173

AN:

1457156

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

724716

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33354

American (AMR)

AF:

0.00

AC:

AN:

44344

Ashkenazi Jewish (ASJ)

AF:

0.0000768

AC:

AN:

26056

East Asian (EAS)

AF:

0.000177

AC:

AN:

39552

South Asian (SAS)

AF:

0.0000466

AC:

AN:

85882

European-Finnish (FIN)

AF:

0.0000952

AC:

AN:

52524

Middle Eastern (MID)

AF:

0.000869

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000130

AC:

144

AN:

1109484

Other (OTH)

AF:

0.0000332

AC:

AN:

60206

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

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

AF:

0.000152

AC:

AN:

151270

Hom.:

Cov.:

AF XY:

0.0000947

AC XY:

AN XY:

73908

show subpopulations

African (AFR)

AF:

0.000170

AC:

AN:

41254

American (AMR)

AF:

0.00

AC:

AN:

15192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.000395

AC:

AN:

5068

South Asian (SAS)

AF:

0.00

AC:

AN:

4788

European-Finnish (FIN)

AF:

0.0000956

AC:

AN:

10456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000192

AC:

AN:

67754

Other (OTH)

AF:

0.00

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 24, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Glu607[17] in exon 2 of the TPRN gene: This variant is not expected to have cl inical significance because it results in an in-frame insertion of 2 glutamic ac id (Glu) residues in a poly-glutamic acid tract, and several in-frame duplicatio ns and deletions of Glu residues have been identified in the general population at relatively high frequencies, indicating that a variable number of glutamic ac id (Glu) repeats is likely tolerated in this region. This variant has been ident ified in 11/87600 chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs139510609). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.16

Mutation Taster

=75/25

polymorphism

(source)

Splicing

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

Publications

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9-137192572-TTCCTCCTCCTCCTCCTCC-TTCCTCCTCCTCCTCCTCCTCCTCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over