Genetic Variant TMPRSS9:p.Thr82Met (chr19-2396641-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001385642.1(TMPRSS9):c.-452C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000516 in 1,607,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

TMPRSS9
NM_001385642.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.438

Publications

3 publications found

Variant links:

Genes affected

TMPRSS9 (HGNC:30079): (transmembrane serine protease 9) The protein encoded by this gene is a membrane-bound type II serine polyprotease that is cleaved to release three different proteases. Two of the proteases are active and can be inhibited by serine protease inhibitors, and one is thought to be catalytically inactive. This gene enhances the invasive capability of pancreatic cancer cells and may be involved in cancer progression. [provided by RefSeq, Jul 2016]

TMPRSS9 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

TMPRSS9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017785192).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385642.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMPRSS9	NM_001395513.1	MANE Select	c.245C>T	p.Thr82Met	missense	Exon 3 of 19	NP_001382442.1	A0A3B3IU58
TMPRSS9	NM_001385642.1		c.-452C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 18	NP_001372571.1
TMPRSS9	NM_182973.3		c.245C>T	p.Thr82Met	missense	Exon 3 of 18	NP_892018.1	Q7Z410

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMPRSS9	ENST00000696167.1	MANE Select	c.245C>T	p.Thr82Met	missense	Exon 3 of 19	ENSP00000512457.1	A0A3B3IU58
TMPRSS9	ENST00000395264.3	TSL:1	n.260C>T		non_coding_transcript_exon	Exon 2 of 10
TMPRSS9	ENST00000648592.1		c.245C>T	p.Thr82Met	missense	Exon 2 of 18	ENSP00000498031.1	A0A3B3IU58

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000148

AC:

AN:

237182

AF XY:

0.000124

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00136

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000467

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.0000488

AC:

AN:

1455408

Hom.:

Cov.:

AF XY:

0.0000484

AC XY:

AN XY:

723518

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33436

American (AMR)

AF:

0.00

AC:

AN:

43424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25888

East Asian (EAS)

AF:

0.000633

AC:

AN:

39470

South Asian (SAS)

AF:

0.0000941

AC:

AN:

85048

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52728

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000279

AC:

AN:

1109572

Other (OTH)

AF:

0.0000831

AC:

AN:

60144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

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:

0.0000788

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41454

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000385

AC:

AN:

5200

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:

0.0000441

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.000138

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000140

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.48

CADD

Benign

1.2

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.0083

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.58

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.0

PhyloP100

-0.44

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.52

REVEL

Benign

0.083

Sift

Benign

0.34

Sift4G

Benign

0.22

Polyphen

0.0010

Vest4

0.17

MVP

0.49

MPC

0.079

ClinPred

0.0037

GERP RS

-3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.019

gMVP

0.32

Mutation Taster

=95/5

polymorphism

(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

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