1-11016874-C-T

Position:

chr1-11016874-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2

The NM_007375.4(TARDBP):c.269C>T(p.Ala90Val) variant causes a missense change. The variant allele was found at a frequency of 0.000416 in 1,614,166 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 1 hom. )

Consequence

TARDBP
NM_007375.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1O:1

Conservation

PhyloP100: 5.89

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TARDBP. . Gene score misZ 3.7095 (greater than the threshold 3.09). Trascript score misZ 5.3115 (greater than threshold 3.09). GenCC has associacion of gene with amyotrophic lateral sclerosis type 10, amyotrophic lateral sclerosis, frontotemporal dementia with motor neuron disease.

BP4

Computational evidence support a benign effect (MetaRNN=0.13806838).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000263 (40/152320) while in subpopulation NFE AF= 0.000558 (38/68040). AF 95% confidence interval is 0.000418. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TARDBP	NM_007375.4 linkuse as main transcript	c.269C>T	p.Ala90Val	missense_variant	3/6	ENST00000240185.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TARDBP	ENST00000240185.8 linkuse as main transcript	c.269C>T	p.Ala90Val	missense_variant	3/6	1	NM_007375.4	P1	Q13148-1

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000558

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000219

AC:

AN:

251440

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000432

AC:

631

AN:

1461846

Hom.:

Cov.:

AF XY:

0.000414

AC XY:

301

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000541

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000263

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000558

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000455

Hom.:

Bravo

AF:

0.000321

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 10

Uncertain:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	May be a variant that is normal or confers susceptibility to FTD/ALS. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Jul 29, 2022	ACMG criteria used to clasify this variant: PM2, PP2 -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TARDBP: PP2, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2022	Variant has been observed in individuals with ALS and Alzheimer disease, as well as in unaffected controls (Winton et al., 2008; Morgan et al., 2017; Sreedharan et al., 2008; van Blitterswijk et al., 2012); Functional studies demonstrate that A90V leads to partial re-localization of TDP-43 from the nucleus, where it normally resides, to the cytoplasm where it forms aggregates; however this alone may not be sufficient to cause ALS/FTD (Wobst et al., 2017; Wilton et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26883171, 19224587, 28510586, 18372902, 23327806, 24143176, 18545701, 25525159, 28889094, 28335005, 28286471, 25442115, 19760257, 18505686, 22456481, 18309045, 28430856, 22645277, 20555136, 31996268, 33151007, 35499795, 34930382, 34412568, 34697451, 35047667) -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 12, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TARDBP function (PMID: 18505686, 24143176, 25442115, 26883171, 28286471, 28335005). 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. ClinVar contains an entry for this variant (Variation ID: 21481). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 18309045, 18372902, 18505686, 18545701, 19224587, 19760257, 20555136, 22456481, 22645277, 23327806, 28430856, 28889094, 31996268). This variant is present in population databases (rs80356715, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 90 of the TARDBP protein (p.Ala90Val). -

TARDBP-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

The TARDBP c.269C>T variant is predicted to result in the amino acid substitution p.Ala90Val. This variant has been reported in unrelated individuals with amyotrophic lateral sclerosis; however, it has also been reported at similar frequencies within control cohorts (see, for example, Czell et al. 2013. PubMed ID: 23327806; Morgan et al. 2017. PubMed ID: 28430856; Sreedharan et al. 2008. PubMed ID: 18309045; van Blitterswijk et al. 2012. PubMed ID: 22645277). This variant is reported in 0.044% of alleles in individuals of European (non-Finnish) descent in gnomAD. Functional studies in cell lines showed the p.Ala90Val resulted in cytoplasmic retention of the TDP-43 protein and the slower kinetics associated with this variant correspond to a delayed disease progression (Winton et al. 2008. PubMed ID: 18505686; Rojas et al. 2023. PubMed ID: 37645251). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Benign

0.42

DEOGEN2

Benign

0.39

.;T;T;T;T;T;T;T;T;T

Eigen

Benign

0.082

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;.;D;.;D;D;D;D;D;D

M_CAP

Benign

0.077

MetaRNN

Benign

0.14

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.4

.;L;L;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.2

.;N;.;.;.;.;N;.;.;.

REVEL

Benign

0.17

Sift

Benign

0.63

.;T;.;.;.;.;T;.;.;.

Sift4G

Benign

1.0

T;T;.;T;T;T;T;.;T;T

Polyphen

0.15

.;B;B;.;.;.;.;.;.;.

Vest4

0.33, 0.33, 0.34, 0.34, 0.33

MVP

0.62

MPC

1.4

ClinPred

0.086

GERP RS

5.4

Varity_R

0.30

gMVP

0.80

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