Genetic Variant TMPRSS13:p.Arg325Gln (chr11-117909941-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001077263.3(TMPRSS13):c.974G>A(p.Arg325Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

TMPRSS13
NM_001077263.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.60

Variant links:

Genes affected

TMPRSS13 (HGNC:29808): (transmembrane serine protease 13) This gene encodes a member of the type II transmembrane serine protease family. The encoded protein contains a type II transmembrane domain, a receptor class A domain, a scavenger receptor cysteine-rich domain and a protease domain. Transmembrane serine proteases are regulated by protease inhibitors and known to function in development, homeostasis, infection, and tumorigenesis. This protein facilitates entry of viruses into host cells by proteolytically cleaving and activating viral envelope glycoproteins. [provided by RefSeq, Aug 2021]

TMPRSS13 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS13	NM_001077263.3 link	c.974G>A	p.Arg325Gln	missense_variant	Exon 8 of 13	ENST00000524993.6	NP_001070731.1	Q9BYE2-6
TMPRSS13	NM_001244995.2 link	c.974G>A	p.Arg325Gln	missense_variant	Exon 8 of 13		NP_001231924.1	Q9BYE2-2
TMPRSS13	NM_001206789.2 link	c.869G>A	p.Arg290Gln	missense_variant	Exon 7 of 12		NP_001193718.1	Q9BYE2-3
TMPRSS13	NM_001206790.2 link	c.974G>A	p.Arg325Gln	missense_variant	Exon 8 of 9		NP_001193719.1	Q9BYE2-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS13	ENST00000524993.6 link	c.974G>A	p.Arg325Gln	missense_variant	Exon 8 of 13	1	NM_001077263.3	ENSP00000434279.1		Q9BYE2-6

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.974G>A (p.R325Q) alteration is located in exon 8 (coding exon 8) of the TMPRSS13 gene. This alteration results from a G to A substitution at nucleotide position 974, causing the arginine (R) at amino acid position 325 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

.;T;.;T;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.86

D;D;D;D;D

MetaSVM

Uncertain

0.55

MutationAssessor

Pathogenic

2.9

.;.;M;.;M

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.2

D;D;D;D;D

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Uncertain

0.012

D;D;D;D;D

Polyphen

1.0

.;D;.;.;.

Vest4

0.87

MVP

0.86

MPC

0.92

ClinPred

0.99

GERP RS

4.4

gMVP

0.95

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