Genetic Variant TMPRSS9:p.Asp1042Asp (chr19-2425932-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP7BS2

The NM_001395513.1(TMPRSS9):c.3126C>T(p.Asp1042Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000853 in 1,594,578 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000092 ( 2 hom. )

Consequence

TMPRSS9
NM_001395513.1 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.559

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP7

Synonymous conserved (PhyloP=-0.559 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS9	NM_001395513.1 link	c.3126C>T	p.Asp1042Asp	synonymous_variant	Exon 19 of 19	ENST00000696167.1	NP_001382442.1
TIMM13	NM_012458.4 link	c.*1016G>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.3126C>T	p.Asp1042Asp	synonymous_variant	Exon 19 of 19		NM_001395513.1	ENSP00000512457.1	A0A3B3IU58
TIMM13	ENST00000215570 link	c.*1016G>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_012458.4	ENSP00000215570.2	Q9Y5L4
TMPRSS9	ENST00000648592.1 link	c.3126C>T	p.Asp1042Asp	synonymous_variant	Exon 18 of 18			ENSP00000498031.1	A0A3B3IU58
TMPRSS9	ENST00000649857.1 link	c.3024C>T	p.Asp1008Asp	synonymous_variant	Exon 18 of 18			ENSP00000497651.1	Q7Z410

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000198

AC:

AN:

231944

Hom.:

AF XY:

0.000323

AC XY:

AN XY:

126750

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00157

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000944

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000915

AC:

132

AN:

1442456

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

104

AN XY:

717750

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.00150

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000271

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.68

DANN

Benign

0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over