Genetic Variant TMPRSS5:p.Ala442Gly (chr11-113689799-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_030770.4(TMPRSS5):c.1325C>G(p.Ala442Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,142 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A442V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

TMPRSS5
NM_030770.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.57

Publications

4 publications found

Variant links:

Genes affected

TMPRSS5 (HGNC:14908): (transmembrane serine protease 5) This gene encodes a protein that belongs to the serine protease family. Serine proteases are known to be involved in many physiological and pathological processes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

TMPRSS5 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

TMPRSS5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030770.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMPRSS5	NM_030770.4	MANE Select	c.1325C>G	p.Ala442Gly	missense	Exon 12 of 13	NP_110397.2	Q9H3S3
TMPRSS5	NM_001288751.2		c.1298C>G	p.Ala433Gly	missense	Exon 12 of 13	NP_001275680.1	F5GX83
TMPRSS5	NM_001288750.2		c.1193C>G	p.Ala398Gly	missense	Exon 11 of 12	NP_001275679.1	F5H2M3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMPRSS5	ENST00000299882.11	TSL:1 MANE Select	c.1325C>G	p.Ala442Gly	missense	Exon 12 of 13	ENSP00000299882.5	Q9H3S3
TMPRSS5	ENST00000545579.6	TSL:1	c.1298C>G	p.Ala433Gly	missense	Exon 12 of 13	ENSP00000441104.1	F5GX83
TMPRSS5	ENST00000538955.5	TSL:1	c.1193C>G	p.Ala398Gly	missense	Exon 11 of 12	ENSP00000445528.1	F5H2M3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00000416

AC:

AN:

240348

AF XY:

0.00000769

show subpopulations

Gnomad AFR exome

AF:

0.0000687

Gnomad AMR exome

AF:

0.00

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

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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.:

Bravo

AF:

0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.35

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.71

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.48

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

2.0

PhyloP100

4.6

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.47

Sift

Uncertain

0.022

Sift4G

Uncertain

0.028

Polyphen

0.64

Vest4

0.38

MutPred

0.73

Loss of stability (P = 0.0969)

MVP

0.84

MPC

0.25

ClinPred

0.41

GERP RS

2.3

Varity_R

0.28

gMVP

0.55

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.57

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.40

Position offset: 5

DS_DL_spliceai

0.57

Position offset: -34

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over