21-42372760-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001256317.3(TMPRSS3):c.*2G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,613,162 control chromosomes in the GnomAD database, including 44,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3547 hom., cov: 31)

Exomes 𝑓: 0.22 ( 40950 hom. )

Consequence

TMPRSS3
NM_001256317.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.324

Publications

15 publications found

Variant links:

Genes affected

TMPRSS3 (HGNC:11877): (transmembrane serine protease 3) This gene encodes a protein that belongs to the serine protease family. The encoded protein contains a serine protease domain, a transmembrane domain, an LDL receptor-like domain, and a scavenger receptor cysteine-rich domain. Serine proteases are known to be involved in a variety of biological processes, whose malfunction often leads to human diseases and disorders. This gene was identified by its association with both congenital and childhood onset autosomal recessive deafness. This gene is expressed in fetal cochlea and many other tissues, and is thought to be involved in the development and maintenance of the inner ear or the contents of the perilymph and endolymph. This gene was also identified as a tumor-associated gene that is overexpressed in ovarian tumors. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2012]

TMPRSS3 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 8
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TMPRSS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 21-42372760-C-T is Benign according to our data. Variant chr21-42372760-C-T is described in ClinVar as Benign. ClinVar VariationId is 46089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256317.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TMPRSS3	NM_001256317.3	MANE Select	c.*2G>A	3_prime_UTR	Exon 13 of 13	NP_001243246.1
TMPRSS3	NM_024022.4		c.*2G>A	3_prime_UTR	Exon 13 of 13	NP_076927.1
TMPRSS3	NM_032404.3		c.*2G>A	3_prime_UTR	Exon 10 of 10	NP_115780.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TMPRSS3	ENST00000644384.2	MANE Select	c.*2G>A	3_prime_UTR	Exon 13 of 13	ENSP00000494414.1
TMPRSS3	ENST00000433957.7	TSL:1	c.*2G>A	3_prime_UTR	Exon 13 of 13	ENSP00000411013.3
TMPRSS3	ENST00000474596.5	TSL:1	n.1235G>A	non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes

AF:

0.188

AC:

28576

AN:

151908

Hom.:

3538

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0719

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.210

Gnomad ASJ

AF:

0.243

Gnomad EAS

AF:

0.560

Gnomad SAS

AF:

0.362

Gnomad FIN

AF:

0.191

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.210

Gnomad OTH

AF:

0.245

GnomAD2 exomes

AF:

0.238

AC:

59947

AN:

251476

AF XY:

0.248

show subpopulations

Gnomad AFR exome

AF:

0.0725

Gnomad AMR exome

AF:

0.157

Gnomad ASJ exome

AF:

0.257

Gnomad EAS exome

AF:

0.566

Gnomad FIN exome

AF:

0.189

Gnomad NFE exome

AF:

0.211

Gnomad OTH exome

AF:

0.235

GnomAD4 exome

AF:

0.225

AC:

328119

AN:

1461136

Hom.:

40950

Cov.:

AF XY:

0.229

AC XY:

166559

AN XY:

726918

show subpopulations

African (AFR)

AF:

0.0687

AC:

2301

AN:

33472

American (AMR)

AF:

0.163

AC:

7309

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.252

AC:

6588

AN:

26126

East Asian (EAS)

AF:

0.543

AC:

21571

AN:

39690

South Asian (SAS)

AF:

0.346

AC:

29824

AN:

86232

European-Finnish (FIN)

AF:

0.189

AC:

10106

AN:

53402

Middle Eastern (MID)

AF:

0.243

AC:

1403

AN:

5764

European-Non Finnish (NFE)

AF:

0.211

AC:

234188

AN:

1111364

Other (OTH)

AF:

0.246

AC:

14829

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

13301

26602

39904

53205

66506

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8332

16664

24996

33328

41660

<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:

0.188

AC:

28591

AN:

152026

Hom.:

3547

Cov.:

AF XY:

0.194

AC XY:

14383

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0717

AC:

2974

AN:

41486

American (AMR)

AF:

0.210

AC:

3204

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.243

AC:

842

AN:

3468

East Asian (EAS)

AF:

0.560

AC:

2888

AN:

5154

South Asian (SAS)

AF:

0.361

AC:

1742

AN:

4820

European-Finnish (FIN)

AF:

0.191

AC:

2022

AN:

10570

Middle Eastern (MID)

AF:

0.252

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.210

AC:

14237

AN:

67934

Other (OTH)

AF:

0.253

AC:

534

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1105

2210

3314

4419

5524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

316

632

948

1264

1580

<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:

0.203

Hom.:

11687

Bravo

AF:

0.184

Asia WGS

AF:

0.454

AC:

1576

AN:

3478

EpiCase

AF:

0.223

EpiControl

AF:

0.223

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive nonsyndromic hearing loss 8 (2)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.5

(source)

DANN

Benign

0.72

PhyloP100

0.32

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over