Genetic Variant TMPRSS4:p.Cys193Ser (chr11-118108891-G-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP3BP4_StrongBP6_ModerateBS2

The NM_019894.4(TMPRSS4):c.578G>C(p.Cys193Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00417 in 1,614,030 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 18 hom. )

Consequence

TMPRSS4
NM_019894.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.71

Publications

10 publications found

Variant links:

Genes affected

TMPRSS4 (HGNC:11878): (transmembrane serine protease 4) This gene encodes a member of the serine protease family. 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 as a gene overexpressed in pancreatic carcinoma. The encoded protein is membrane bound with a N-terminal anchor sequence and a glycosylated extracellular region containing the serine protease domain. The protein has been found to promote SARS-CoV-2 entry into host cells. [provided by RefSeq, Aug 2021]

TMPRSS4 Gene-Disease associations (from GenCC):

autosomal recessive cerebral atrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TMPRSS4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.030412793).

BP6

Variant 11-118108891-G-C is Benign according to our data. Variant chr11-118108891-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2642410.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019894.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMPRSS4	NM_019894.4	MANE Select	c.578G>C	p.Cys193Ser	missense	Exon 7 of 13	NP_063947.2	Q9NRS4-1
TMPRSS4	NM_001173551.2		c.572G>C	p.Cys191Ser	missense	Exon 7 of 13	NP_001167022.2	Q9NRS4-3
TMPRSS4	NM_001083947.2		c.563G>C	p.Cys188Ser	missense	Exon 7 of 13	NP_001077416.2	Q9NRS4-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMPRSS4	ENST00000437212.8	TSL:1 MANE Select	c.578G>C	p.Cys193Ser	missense	Exon 7 of 13	ENSP00000416037.3	Q9NRS4-1
TMPRSS4	ENST00000522824.5	TSL:1	c.563G>C	p.Cys188Ser	missense	Exon 7 of 13	ENSP00000430547.1	Q9NRS4-2
TMPRSS4	ENST00000714375.1		n.578G>C		non_coding_transcript_exon	Exon 7 of 12	ENSP00000519642.1	A0AAQ5BHV3

Frequencies

GnomAD3 genomes

AF:

0.00354

AC:

539

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00498

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00594

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00509

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00384

AC:

964

AN:

251000

AF XY:

0.00367

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.00339

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00735

Gnomad NFE exome

AF:

0.00526

Gnomad OTH exome

AF:

0.00506

GnomAD4 exome

AF:

0.00424

AC:

6197

AN:

1461726

Hom.:

Cov.:

AF XY:

0.00416

AC XY:

3027

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33468

American (AMR)

AF:

0.00396

AC:

177

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00210

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000858

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00696

AC:

372

AN:

53414

Middle Eastern (MID)

AF:

0.00815

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00464

AC:

5159

AN:

1111916

Other (OTH)

AF:

0.00477

AC:

288

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

307

614

922

1229

1536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

190

380

570

760

950

<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:

0.00354

AC:

539

AN:

152304

Hom.:

Cov.:

AF XY:

0.00318

AC XY:

237

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41568

American (AMR)

AF:

0.00497

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00104

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00594

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00509

AC:

346

AN:

68034

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

107

134

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:

0.00443

Hom.:

Bravo

AF:

0.00351

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00417

AC:

506

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00513

EpiControl

AF:

0.00498

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.58

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.030

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.1

PhyloP100

5.7

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-9.6

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.73

MutPred

0.75

Gain of disorder (P = 0.0089)

MVP

0.90

MPC

0.63

ClinPred

0.079

GERP RS

4.9

Varity_R

0.94

gMVP

0.87

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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