Genetic Variant TMPRSS11B:p.Ile242Val (chr4-68229479-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_182502.3(TMPRSS11B):c.724A>G(p.Ile242Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 1,612,296 control chromosomes in the GnomAD database, including 481,149 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.70 ( 39299 hom., cov: 32)

Exomes 𝑓: 0.77 ( 441850 hom. )

Consequence

TMPRSS11B
NM_182502.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.52

Publications

25 publications found

Variant links:

Genes affected

TMPRSS11B (HGNC:25398): (transmembrane serine protease 11B) Enables serine-type peptidase activity. Predicted to be involved in proteolysis. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMPRSS11B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.245127E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TMPRSS11B	NM_182502.3 link	c.724A>G	p.Ile242Val	missense_variant	Exon 8 of 10	ENST00000332644.6	NP_872308.2
TMPRSS11B	XM_011531608.3 link	c.724A>G	p.Ile242Val	missense_variant	Exon 8 of 11		XP_011529910.1
TMPRSS11B	XM_011531609.1 link	c.687-127A>G		intron_variant	Intron 7 of 7		XP_011529911.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS11B	ENST00000332644.6 link	c.724A>G	p.Ile242Val	missense_variant	Exon 8 of 10	1	NM_182502.3	ENSP00000330475.5
TMPRSS11B	ENST00000510856.1 link	n.200A>G		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.705

AC:

107069

AN:

151940

Hom.:

39286

Cov.:

show subpopulations

Gnomad AFR

AF:

0.518

Gnomad AMI

AF:

0.802

Gnomad AMR

AF:

0.641

Gnomad ASJ

AF:

0.701

Gnomad EAS

AF:

0.991

Gnomad SAS

AF:

0.874

Gnomad FIN

AF:

0.828

Gnomad MID

AF:

0.652

Gnomad NFE

AF:

0.779

Gnomad OTH

AF:

0.696

GnomAD2 exomes

AF:

0.752

AC:

188558

AN:

250592

AF XY:

0.766

show subpopulations

Gnomad AFR exome

AF:

0.508

Gnomad AMR exome

AF:

0.551

Gnomad ASJ exome

AF:

0.701

Gnomad EAS exome

AF:

0.995

Gnomad FIN exome

AF:

0.826

Gnomad NFE exome

AF:

0.771

Gnomad OTH exome

AF:

0.730

GnomAD4 exome

AF:

0.774

AC:

1130356

AN:

1460238

Hom.:

441850

Cov.:

AF XY:

0.777

AC XY:

564744

AN XY:

726430

show subpopulations

African (AFR)

AF:

0.515

AC:

17215

AN:

33412

American (AMR)

AF:

0.561

AC:

25027

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.699

AC:

18246

AN:

26100

East Asian (EAS)

AF:

0.997

AC:

39553

AN:

39668

South Asian (SAS)

AF:

0.863

AC:

74328

AN:

86112

European-Finnish (FIN)

AF:

0.823

AC:

43912

AN:

53386

Middle Eastern (MID)

AF:

0.651

AC:

3738

AN:

5740

European-Non Finnish (NFE)

AF:

0.776

AC:

862526

AN:

1110858

Other (OTH)

AF:

0.759

AC:

45811

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

11693

23385

35078

46770

58463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20476

40952

61428

81904

102380

<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:

0.704

AC:

107114

AN:

152058

Hom.:

39299

Cov.:

AF XY:

0.711

AC XY:

52841

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.517

AC:

21418

AN:

41424

American (AMR)

AF:

0.641

AC:

9784

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.701

AC:

2429

AN:

3466

East Asian (EAS)

AF:

0.991

AC:

5138

AN:

5186

South Asian (SAS)

AF:

0.876

AC:

4223

AN:

4820

European-Finnish (FIN)

AF:

0.828

AC:

8758

AN:

10582

Middle Eastern (MID)

AF:

0.660

AC:

194

AN:

294

European-Non Finnish (NFE)

AF:

0.779

AC:

52970

AN:

68000

Other (OTH)

AF:

0.697

AC:

1470

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1465

2931

4396

5862

7327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

828

1656

2484

3312

4140

<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:

0.747

Hom.:

144788

Bravo

AF:

0.679

TwinsUK

AF:

0.781

AC:

2895

ALSPAC

AF:

0.779

AC:

3003

ESP6500AA

AF:

0.523

AC:

2303

ESP6500EA

AF:

0.779

AC:

6697

ExAC

AF:

0.756

AC:

91755

Asia WGS

AF:

0.857

AC:

2981

AN:

3476

EpiCase

AF:

0.756

EpiControl

AF:

0.755

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.16

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.59

MetaRNN

Benign

9.2e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.28

PhyloP100

1.5

PrimateAI

Benign

0.30

PROVEAN

Benign

0.34

REVEL

Benign

0.12

Sift

Benign

0.61

Sift4G

Benign

0.57

Polyphen

0.0030

Vest4

0.047

MPC

0.026

ClinPred

0.0038

GERP RS

0.64

Varity_R

0.056

gMVP

0.32

Mutation Taster

=97/3

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over