1-11022209-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PP2PP5BP4BS1_SupportingBS2

The NM_007375.4(TARDBP):c.800A>G(p.Asn267Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

TARDBP
NM_007375.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:3O:1

Conservation

PhyloP100: 3.44

Publications

41 publications found

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 Gene-Disease associations (from GenCC):

immunodeficiency due to MASP-2 deficiency
Inheritance: AR Classification: STRONG Submitted by: Laboratory for Molecular Medicine

MASP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP2

Missense variant in the TARDBP gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 3.7095 (above the threshold of 3.09). Trascript score misZ: 5.3115 (above the threshold of 3.09). GenCC associations: The gene is linked to amyotrophic lateral sclerosis type 10, frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis, inclusion body myositis.

PP5

Variant 1-11022209-A-G is Pathogenic according to our data. Variant chr1-11022209-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21482.

BP4

Computational evidence support a benign effect (MetaRNN=0.046908468). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000722 (11/152340) while in subpopulation SAS AF = 0.000829 (4/4828). AF 95% confidence interval is 0.000283. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TARDBP	NM_007375.4 link	c.800A>G	p.Asn267Ser	missense_variant	Exon 6 of 6	ENST00000240185.8	NP_031401.1	Q13148-1Q9H256A0A024R4E2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TARDBP	ENST00000240185.8 link	c.800A>G	p.Asn267Ser	missense_variant	Exon 6 of 6	1	NM_007375.4	ENSP00000240185.4		Q13148-1
TARDBP	ENST00000649624.1 link	c.768+32A>G		intron_variant	Intron 5 of 5			ENSP00000497327.1		A0A0A0N0M3

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152222

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:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000757

AC:

AN:

251128

AF XY:

0.0000663

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1461666

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.000112

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000278

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000868

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000477

AC:

AN:

1111836

Other (OTH)

AF:

0.0000497

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000722

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41584

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000829

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68038

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.540

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000668

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 10

Pathogenic:1Uncertain:1Other:1

Aug 10, 2024

Neurogenetics, Cyprus Institute of Neurology and Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TARDBP c.800A>G (NM_007375.4) sequence change replaces Asparagine to Serine at codon 267 of TAR DNA-binding protein 43 (p.Asn267Ser). TARDBP c.800A>G has been reported in in ClinVar in at least 5 cases with Amyotrophic lateral sclerosis. The variant is present at low allele frequencies population databases. Missense variant in a gene with low rate of benign missense mutations and for which missense mutation is a common mechanism of a disease (PP2) and 38 pathogenic or likely pathogenic reported variants were found in a 531bp region surrounding this variant in exon 6 within the region 11082180-11082711 without any missense benign variants (PM1). In summary, the currently available evidence indicates that the variant is Likely pathogenic. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Aug 23, 2022

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TARDBP: PM1, PM2, PS4:Moderate, PS3:Supporting, BP4 -

TARDBP-related disorder

Pathogenic:1

Jan 26, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TARDBP c.800A>G variant is predicted to result in the amino acid substitution p.Asn267Ser. This variant has been reported in multiple unrelated individuals with TARDBP-related conditions such as amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), corticobasal syndrome (CBS), Parkinson disease (PD), and Alzheimer disease (AD, see for example: Corrado et al. 2009. PubMed ID: 19224587; Borroni et al. 2009. PubMed ID: 19655382; Huey et al. 2011. PubMed ID: 21943958; Rayaprolu et al. 2012. PubMed ID: 23231971; Fernández et al. 2017. PubMed ID: 29091718). This variant is reported in 0.023% of alleles in individuals of South Asian descent in gnomAD. This missense variant is located within the known mutational hotspot of TARDBP. This variant is interpreted as likely pathogenic. -

FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, TARDBP-RELATED

Pathogenic:1

Mar 25, 2022

DASA

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.800A>G;p.(Asn267Ser) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 21482;PMID: 20301761; PMID: 29895397; PMID: 19224587)-PS4. The variant is present at low allele frequencies population databases (rs80356718 – gnomAD 0.0007566%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br.) - PM2_supporting. Missense variant in TARDBP that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. In summary, the currently available evidence indicates that the variant is likely pathogenic -

Inborn genetic diseases

Uncertain:1

Jun 07, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.800A>G (p.N267S) alteration is located in exon 6 (coding exon 5) of the TARDBP gene. This alteration results from a A to G substitution at nucleotide position 800, causing the asparagine (N) at amino acid position 267 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Amyotrophic lateral sclerosis type 10;C3150169:FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, TARDBP-RELATED

Uncertain:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 267 of the TARDBP protein (p.Asn267Ser). This variant is present in population databases (rs80356718, gnomAD 0.03%). This missense change has been observed in individual(s) with TARDBP-related conditions (PMID: 19224587, 19655382, 20645878, 21943958, 23231971, 25138285, 28573484, 29801890, 29895397, 36527522). ClinVar contains an entry for this variant (Variation ID: 21482). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TARDBP protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.39

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

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.85

.;D;.;T;T;D;D;D;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.047

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

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.0

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

PhyloP100

3.4

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.7

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

REVEL

Benign

0.18

Sift

Benign

0.27

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

Sift4G

Benign

0.37

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

Polyphen

0.0070

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

Vest4

0.18

MVP

0.74

MPC

0.73

ClinPred

0.058

GERP RS

2.2

PromoterAI

0.027

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.59

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over