1-11022290-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP2PP5_Very_Strong

The NM_007375.4(TARDBP):c.881G>T(p.Gly294Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G294A) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TARDBP
NM_007375.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 4.63

Variant links:

Genes affected

TARDBP (HGNC:11571): (TAR DNA binding protein) HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrated DNA during the replicative cycle. Activation of HIV-1 gene expression by the transactivator Tat is dependent on an RNA regulatory element (TAR) located downstream of the transcription initiation site. The protein encoded by this gene is a transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription. In addition, this protein regulates alternate splicing of the CFTR gene. A similar pseudogene is present on chromosome 20. [provided by RefSeq, Jul 2008]

TARDBP links:

MASP2 (HGNC:6902): (MBL associated serine protease 2) This gene encodes a member of the peptidase S1 family of serine proteases. The encoded preproprotein is proteolytically processed to generate A and B chains that heterodimerize to form the mature protease. This protease cleaves complement components C2 and C4 in order to generate C3 convertase in the lectin pathway of the complement system. The encoded protease also plays a role in the coagulation cascade through cleavage of prothrombin to form thrombin. Myocardial infarction and acute stroke patients exhibit reduced serum concentrations of the encoded protein. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

MASP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_007375.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-11022290-G-C is described in Lovd as [Pathogenic].

PP2

Missense variant where missense usually causes diseases, TARDBP

PP5

Variant 1-11022290-G-T is Pathogenic according to our data. Variant chr1-11022290-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 21484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11022290-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TARDBP	NM_007375.4 linkuse as main transcript	c.881G>T	p.Gly294Val	missense_variant	6/6	ENST00000240185.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TARDBP	ENST00000240185.8 linkuse as main transcript	c.881G>T	p.Gly294Val	missense_variant	6/6	1	NM_007375.4	P1	Q13148-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152192

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251162

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135736

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461670

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727144

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74346

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 10

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 23, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Amyotrophic lateral sclerosis type 10;C3150169:TARDBP-related frontotemporal dementia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 294 of the TARDBP protein (p.Gly294Val). This variant is present in population databases (rs80356721, gnomAD 0.004%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 19864664, 21651514, 29630989). ClinVar contains an entry for this variant (Variation ID: 21484). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TARDBP protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects TARDBP function (PMID: 25090004). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 26, 2021

The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database [gnomAD], Cambridge, MA [URL: http://gnomad.broadinstitute.org]). Reports of this variant in asymptomatic individuals well past typical age of onset suggest this variant exhibits reduced penetrance (PMID: 19224587, 22722621, 31852254). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Experiments in patient-derived cell lines showed aberrant stress granule formation and disassembly, as well as severely impaired organelle transport along neuronal axons (PMID: 27570075, 29630989). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.32

Cadd

Benign

Dann

Benign

0.95

DEOGEN2

Uncertain

0.50

D;D;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.92

M_CAP

Uncertain

0.087

MetaRNN

Uncertain

0.70

D;D;D

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.7

L;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.75

N;.;.

REVEL

Uncertain

0.53

Sift

Benign

0.26

T;.;.

Sift4G

Benign

0.27

T;.;D

Polyphen

0.14

B;B;.

Vest4

0.86

MutPred

0.82

Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);.;

MVP

0.98

MPC

1.3

ClinPred

0.13

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.93

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over