19-2426039-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001395513.1(TMPRSS9):c.3233C>T(p.Thr1078Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,609,174 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 43 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 47 hom. )

Consequence

TMPRSS9
NM_001395513.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.02

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 links:

TIMM13 (HGNC:11816): (translocase of inner mitochondrial membrane 13) This gene encodes a member of the evolutionarily conserved TIMM (translocase of inner mitochondrial membrane) family of proteins that function as chaperones in the import of proteins from the cytoplasm into the mitochondrial inner membrane. Proteins of this family play a role in collecting substrate proteins from the translocase of the outer mitochondrial membrane (TOM) complex and delivering them to either the sorting and assembly machinery in the outer mitochondrial membrane (SAM) complex or the TIMM22 complex in the inner mitochondrial membrane. The encoded protein and the translocase of mitochondrial inner membrane 8a protein form a 70 kDa complex in the intermembrane space. [provided by RefSeq, Jul 2013]

TIMM13 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011241078).

BP6

Variant 19-2426039-C-T is Benign according to our data. Variant chr19-2426039-C-T is described in ClinVar as [Benign]. Clinvar id is 783812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (1990/152258) while in subpopulation AFR AF = 0.0448 (1860/41520). AF 95% confidence interval is 0.0431. There are 43 homozygotes in GnomAd4. There are 979 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS9	NM_001395513.1 link	c.3233C>T	p.Thr1078Ile	missense_variant	Exon 19 of 19	ENST00000696167.1	NP_001382442.1
TIMM13	NM_012458.4 link	c.*909G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000215570.8	NP_036590.1	Q9Y5L4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMPRSS9	ENST00000696167.1 link	c.3233C>T	p.Thr1078Ile	missense_variant	Exon 19 of 19		NM_001395513.1	ENSP00000512457.1	A0A3B3IU58
TIMM13	ENST00000215570 link	c.*909G>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_012458.4	ENSP00000215570.2	Q9Y5L4
TMPRSS9	ENST00000648592.1 link	c.3233C>T	p.Thr1078Ile	missense_variant	Exon 18 of 18			ENSP00000498031.1	A0A3B3IU58
TMPRSS9	ENST00000649857.1 link	c.3131C>T	p.Thr1044Ile	missense_variant	Exon 18 of 18			ENSP00000497651.1	Q7Z410

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1984

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0448

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00517

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00907

GnomAD2 exomes

AF:

0.00331

AC:

809

AN:

244376

AF XY:

0.00241

show subpopulations

Gnomad AFR exome

AF:

0.0423

Gnomad AMR exome

AF:

0.00254

Gnomad ASJ exome

AF:

0.000307

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000374

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.00151

AC:

2200

AN:

1456916

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

941

AN XY:

724904

show subpopulations

Gnomad4 AFR exome

AF:

0.0460

AC:

1522

AN:

33110

Gnomad4 AMR exome

AF:

0.00305

AC:

134

AN:

43902

Gnomad4 ASJ exome

AF:

0.000309

AC:

AN:

25892

Gnomad4 EAS exome

AF:

0.0000254

AC:

AN:

39390

Gnomad4 SAS exome

AF:

0.000128

AC:

AN:

85774

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

52538

Gnomad4 NFE exome

AF:

0.000256

AC:

284

AN:

1110418

Gnomad4 Remaining exome

AF:

0.00351

AC:

211

AN:

60168

Heterozygous variant carriers

112

224

336

448

560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.0131

AC:

1990

AN:

152258

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

979

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0448

AC:

0.0447977

AN:

0.0447977

Gnomad4 AMR

AF:

0.00516

AC:

0.00516272

AN:

0.00516272

Gnomad4 ASJ

AF:

0.000288

AC:

0.000288018

AN:

0.000288018

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000441

AC:

0.000441138

AN:

0.000441138

Gnomad4 OTH

AF:

0.00898

AC:

0.00897921

AN:

0.00897921

Heterozygous variant carriers

184

275

367

459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00604

Hom.:

Bravo

AF:

0.0146

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0422

AC:

186

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00418

AC:

507

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 03, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;.;T

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.80

.;T;T

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Pathogenic

3.2

M;.;M

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.6

.;.;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

.;.;D

Sift4G

Uncertain

0.0020

.;.;D

Polyphen

1.0

D;.;D

Vest4

0.81

MVP

0.96

MPC

0.45

ClinPred

0.034

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.60

gMVP

0.71

Mutation Taster

=89/11

polymorphism

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over