Genetic Variant TMPRSS9:p.Thr60Arg (chr19-2396575-C-G) – 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_001395513.1(TMPRSS9):c.179C>G(p.Thr60Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T60M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TMPRSS9
NM_001395513.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.338

Publications

0 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:

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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=0.29699075).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395513.1. 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.179C>G	p.Thr60Arg	missense	Exon 3 of 19	NP_001382442.1	A0A3B3IU58
TMPRSS9	NM_182973.3		c.179C>G	p.Thr60Arg	missense	Exon 3 of 18	NP_892018.1	Q7Z410
TMPRSS9	NM_001385642.1		c.-518C>G		5_prime_UTR	Exon 2 of 18	NP_001372571.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMPRSS9	ENST00000696167.1	MANE Select	c.179C>G	p.Thr60Arg	missense	Exon 3 of 19	ENSP00000512457.1	A0A3B3IU58
TMPRSS9	ENST00000395264.3	TSL:1	n.194C>G		non_coding_transcript_exon	Exon 2 of 10
TMPRSS9	ENST00000648592.1		c.179C>G	p.Thr60Arg	missense	Exon 2 of 18	ENSP00000498031.1	A0A3B3IU58

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458246

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725036

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.00

AC:

AN:

44106

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25986

East Asian (EAS)

AF:

0.00

AC:

AN:

39560

South Asian (SAS)

AF:

0.00

AC:

AN:

85394

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110642

Other (OTH)

AF:

0.00

AC:

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.029

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.56

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.30

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

1.9

PhyloP100

-0.34

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.52

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.010

Polyphen

0.53

Vest4

0.46

MutPred

0.54

Gain of MoRF binding (P = 0.0081)

MVP

0.64

MPC

0.33

ClinPred

0.79

GERP RS

-3.2

Varity_R

0.25

gMVP

0.53

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

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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