NM_001128228.3:c.1842_1844dupGGA

Variant names:

• chr9-137192572-T-TTCC
• rs376810326
• NM_001128228.3:c.1842_1844dupGGA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001128228.3(TPRN):​c.1842_1844dupGGA​(p.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 0.00135 in 1,608,350 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: TPRN NM_001128228.3 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001128228.3
• BP6: Variant 9-137192572-T-TTCC is Benign according to our data. Variant chr9-137192572-T-TTCC is described in ClinVar as Benign. ClinVar VariationId is 43961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00225 (340/151268) while in subpopulation EAS AF = 0.0166 (84/5068). AF 95% confidence interval is 0.0137. There are 1 homozygotes in GnomAd4. There are 165 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128228.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPRN	NM_001128228.3	MANE Select	c.1842_1844dupGGA	p.Glu615dup	disruptive_inframe_insertion	Exon 2 of 4	NP_001121700.2	Q4KMQ1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPRN	ENST00000409012.6	TSL:1 MANE Select	c.1842_1844dupGGA	p.Glu615dup	disruptive_inframe_insertion	Exon 2 of 4	ENSP00000387100.4	Q4KMQ1-1
	TPRN	ENST00000477345.1	TSL:1	n.2563_2565dupGGA		non_coding_transcript_exon	Exon 1 of 3
	TPRN	ENST00000961754.1		c.1776_1778dupGGA	p.Glu593dup	disruptive_inframe_insertion	Exon 2 of 4	ENSP00000631813.1

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 338 AN: 151156 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00348

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00310

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0167

Gnomad SAS AF: 0.00501

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000443

Gnomad OTH AF: 0.00434

GnomAD2 exomes AF: 0.00296 AC: 622 AN: 209928 AF XY: 0.00284

Gnomad AFR exome AF: 0.00334

Gnomad AMR exome AF: 0.00152

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.0213

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000609

Gnomad OTH exome AF: 0.00208

GnomAD4 exome AF: 0.00125 AC: 1825 AN: 1457082 Hom.: 5 Cov.: 31 AF XY: 0.00131 AC XY: 948 AN XY: 724676

African (AFR) AF: 0.00390 AC: 130 AN: 33352

American (AMR) AF: 0.00151 AC: 67 AN: 44342

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26056

East Asian (EAS) AF: 0.0170 AC: 673 AN: 39552

South Asian (SAS) AF: 0.00483 AC: 415 AN: 85878

European-Finnish (FIN) AF: 0.0000571 AC: 3 AN: 52522

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5754

European-Non Finnish (NFE) AF: 0.000343 AC: 380 AN: 1109424

Other (OTH) AF: 0.00239 AC: 144 AN: 60202

GnomAD4 genome AF: 0.00225 AC: 340 AN: 151268 Hom.: 1 Cov.: 33 AF XY: 0.00223 AC XY: 165 AN XY: 73906

African (AFR) AF: 0.00349 AC: 144 AN: 41252

American (AMR) AF: 0.00309 AC: 47 AN: 15192

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

East Asian (EAS) AF: 0.0166 AC: 84 AN: 5068

South Asian (SAS) AF: 0.00501 AC: 24 AN: 4788

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000443 AC: 30 AN: 67754

Other (OTH) AF: 0.00525 AC: 11 AN: 2096

Alfa AF: 0.000183 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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; COSMIC: COSV58808995; COSMIC: COSV58808995;