rs80356718

Positions:

chr1-11022209-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PM1PP2PP5BP4BS1_SupportingBS2

The ENST00000240185.8(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. 15/21 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 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

TARDBP
ENST00000240185.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.44

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 Likely_benign. Variant got -2 ACMG points.

PM1

In a region_of_interest Disordered (size 42) in uniprot entity TADBP_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) in ENST00000240185.8

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.

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 id is 21482.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=3, not_provided=1}. Variant chr1-11022209-A-G is described in Lovd as [Pathogenic].

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 male gnomad4 subpopulation. Median coverage is 33. 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 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TARDBP	NM_007375.4 linkuse as main transcript	c.800A>G	p.Asn267Ser	missense_variant	6/6	ENST00000240185.8	NP_031401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TARDBP	ENST00000240185.8 linkuse as main transcript	c.800A>G	p.Asn267Ser	missense_variant	6/6	1	NM_007375.4	ENSP00000240185	P1	Q13148-1

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

GnomAD3 exomes

AF:

0.0000757

AC:

AN:

251128

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135718

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 SAS exome

AF:

0.000229

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74494

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:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.0000547

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:3Uncertain:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 10

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 23, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

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

TARDBP-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 26, 2024

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. -

TARDBP-related frontotemporal dementia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

DASA

Mar 25, 2022

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

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:TARDBP-related frontotemporal dementia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 08, 2023

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). 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. 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: 21482). This missense change has been observed in individual(s) with TARDBP-related conditions (PMID: 19224587, 19655382, 20645878, 21943958, 23231971, 25138285, 28573484, 29801890, 29895397). This variant is present in population databases (rs80356718, gnomAD 0.03%). -

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

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;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

A;A;A

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.59

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

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