Genetic Variant TMPRSS5:p.Arg418Leu (chr11-113689871-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_030770.4(TMPRSS5):c.1253G>T(p.Arg418Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,426,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. R418H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

TMPRSS5
NM_030770.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.153

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35103577).

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.1253G>T	p.Arg418Leu	missense	Exon 12 of 13	NP_110397.2	Q9H3S3
TMPRSS5	NM_001288751.2		c.1226G>T	p.Arg409Leu	missense	Exon 12 of 13	NP_001275680.1	F5GX83
TMPRSS5	NM_001288750.2		c.1121G>T	p.Arg374Leu	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.1253G>T	p.Arg418Leu	missense	Exon 12 of 13	ENSP00000299882.5	Q9H3S3
TMPRSS5	ENST00000545579.6	TSL:1	c.1226G>T	p.Arg409Leu	missense	Exon 12 of 13	ENSP00000441104.1	F5GX83
TMPRSS5	ENST00000538955.5	TSL:1	c.1121G>T	p.Arg374Leu	missense	Exon 11 of 12	ENSP00000445528.1	F5H2M3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000280

AC:

AN:

1426318

Hom.:

Cov.:

AF XY:

0.00000566

AC XY:

AN XY:

706198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32580

American (AMR)

AF:

0.00

AC:

AN:

39334

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25452

East Asian (EAS)

AF:

0.0000267

AC:

AN:

37454

South Asian (SAS)

AF:

0.0000370

AC:

AN:

81120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51058

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094470

Other (OTH)

AF:

0.00

AC:

AN:

59132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.17

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.056

MetaRNN

Benign

0.35

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.29

PhyloP100

0.15

PrimateAI

Benign

0.22

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.21

Sift

Benign

0.15

Sift4G

Benign

0.16

Polyphen

0.18

Vest4

0.58

MutPred

0.70

Gain of catalytic residue at W417 (P = 0.122)

MVP

0.35

MPC

0.33

ClinPred

0.68

GERP RS

-6.3

Varity_R

0.20

gMVP

0.69

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over