Genetic Variant TMPRSS3:c.*815A>G (chr21-42371947-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001256317.3(TMPRSS3):c.*815A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0084 in 454,588 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0078 ( 13 hom., cov: 33)

Exomes 𝑓: 0.0087 ( 24 hom. )

Consequence

TMPRSS3
NM_001256317.3 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.179

Publications

2 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: Labcorp Genetics (formerly Invitae), PanelApp Australia
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 21-42371947-T-C is Benign according to our data. Variant chr21-42371947-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 340040.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00781 (1189/152264) while in subpopulation NFE AF = 0.0119 (811/68018). AF 95% confidence interval is 0.0112. There are 13 homozygotes in GnomAd4. There are 565 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

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	UniProt
TMPRSS3	NM_001256317.3	MANE Select	c.*815A>G	3_prime_UTR	Exon 13 of 13	NP_001243246.1	P57727-5
TMPRSS3	NM_024022.4		c.*815A>G	3_prime_UTR	Exon 13 of 13	NP_076927.1	P57727-1
TMPRSS3	NM_032404.3		c.*815A>G	3_prime_UTR	Exon 10 of 10	NP_115780.1	P57727-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TMPRSS3	ENST00000644384.2	MANE Select	c.*815A>G	3_prime_UTR	Exon 13 of 13	ENSP00000494414.1	P57727-5
TMPRSS3	ENST00000433957.7	TSL:1	c.*815A>G	3_prime_UTR	Exon 13 of 13	ENSP00000411013.3	P57727-1
TMPRSS3	ENST00000474596.5	TSL:1	n.2048A>G	non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes

AF:

0.00782

AC:

1190

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00995

Gnomad ASJ

AF:

0.0239

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.00764

GnomAD2 exomes

AF:

0.00815

AC:

1116

AN:

136970

AF XY:

0.00810

show subpopulations

Gnomad AFR exome

AF:

0.00264

Gnomad AMR exome

AF:

0.00454

Gnomad ASJ exome

AF:

0.0226

Gnomad EAS exome

AF:

0.000187

Gnomad FIN exome

AF:

0.00204

Gnomad NFE exome

AF:

0.0118

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.00870

AC:

2631

AN:

302324

Hom.:

Cov.:

AF XY:

0.00833

AC XY:

1436

AN XY:

172304

show subpopulations

African (AFR)

AF:

0.00304

AC:

AN:

8554

American (AMR)

AF:

0.00473

AC:

129

AN:

27274

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

246

AN:

10786

East Asian (EAS)

AF:

0.00

AC:

AN:

9348

South Asian (SAS)

AF:

0.00396

AC:

236

AN:

59648

European-Finnish (FIN)

AF:

0.00180

AC:

AN:

12748

Middle Eastern (MID)

AF:

0.00870

AC:

AN:

1150

European-Non Finnish (NFE)

AF:

0.0116

AC:

1848

AN:

158764

Other (OTH)

AF:

0.00804

AC:

113

AN:

14052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

182

364

546

728

910

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:

0.00781

AC:

1189

AN:

152264

Hom.:

Cov.:

AF XY:

0.00759

AC XY:

565

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00181

AC:

AN:

41544

American (AMR)

AF:

0.00993

AC:

152

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0239

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00477

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

811

AN:

68018

Other (OTH)

AF:

0.00756

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

130

195

260

325

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0125

Hom.:

Bravo

AF:

0.00753

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive nonsyndromic hearing loss 8 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.49

(source)

DANN

Benign

0.80

PhyloP100

-0.18

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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