dbSNP rs201007237: TMPRSS3:p.Val116Ala (chr21-42388502-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 5P and 13B. PM1PM5PP2BP4_StrongBP6BS1BS2

The NM_001256317.3(TMPRSS3):c.347T>C(p.Val116Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,614,090 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V116M) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00049 ( 3 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

TMPRSS3
NM_001256317.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 2.40

Publications

0 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 -8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_001256317.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-42388503-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 432009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 41 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Trascript score misZ: 0.22926 (below the threshold of 3.09). GenCC associations: The gene is linked to hearing loss, autosomal recessive, autosomal recessive nonsyndromic hearing loss 8, nonsyndromic genetic hearing loss.

BP4

Computational evidence support a benign effect (MetaRNN=0.0480206).

BP6

Variant 21-42388502-A-G is Benign according to our data. Variant chr21-42388502-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46117.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000486 (74/152198) while in subpopulation AMR AF = 0.00484 (74/15292). AF 95% confidence interval is 0.00395. There are 3 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 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	HGVSp	Effect	Exon Rank	Protein	UniProt
TMPRSS3	NM_001256317.3	MANE Select	c.347T>C	p.Val116Ala	missense	Exon 5 of 13	NP_001243246.1	P57727-5
TMPRSS3	NM_024022.4		c.347T>C	p.Val116Ala	missense	Exon 5 of 13	NP_076927.1	P57727-1
TMPRSS3	NM_032405.2		c.347T>C	p.Val116Ala	missense	Exon 5 of 9	NP_115781.1	P57727-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMPRSS3	ENST00000644384.2	MANE Select	c.347T>C	p.Val116Ala	missense	Exon 5 of 13	ENSP00000494414.1	P57727-5
TMPRSS3	ENST00000433957.7	TSL:1	c.347T>C	p.Val116Ala	missense	Exon 5 of 13	ENSP00000411013.3	P57727-1
TMPRSS3	ENST00000398397.3	TSL:1	c.347T>C	p.Val116Ala	missense	Exon 5 of 9	ENSP00000381434.3	P57727-3

Frequencies

GnomAD3 genomes

AF:

0.000486

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00484

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:

0.000123

AC:

AN:

251430

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000896

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:

0.0000239

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000760

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112010

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.000486

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41430

American (AMR)

AF:

0.00484

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.0000734

Hom.:

Bravo

AF:

0.000484

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.13

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.62

M_CAP

Benign

0.030

MetaRNN

Benign

0.048

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.7

PhyloP100

2.4

PrimateAI

Benign

0.39

PROVEAN

Benign

-2.2

REVEL

Benign

0.070

Sift

Benign

0.33

Sift4G

Benign

0.17

Polyphen

0.016

Vest4

0.30

MutPred

0.60

Loss of stability (P = 0.0034)

MVP

0.37

MPC

0.15

ClinPred

0.072

GERP RS

0.98

Varity_R

0.075

gMVP

0.65

Mutation Taster

=46/54

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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