rs80356726

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_007375.4(TARDBP):c.943G>A(p.Ala315Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,670 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A315V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TARDBP
NM_007375.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.21

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 17 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr1-11022353-C-A is described in Lovd as [Pathogenic].

PP2

Missense variant where missense usually causes diseases, TARDBP

PP3

BayesDel_addAF computational evidence supports a deleterious effect, 0.252

PP5

Variant 1-11022352-G-A is Pathogenic according to our data. Variant chr1-11022352-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11022352-G-A 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.943G>A	p.Ala315Thr	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.943G>A	p.Ala315Thr	missense_variant	6/6	1	NM_007375.4	P1	Q13148-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251130

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135718

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

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:

0.00

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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:2Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2008	- -
not provided, no classification provided	literature only	GeneReviews	-	Convincing evidence of segregation. -
Pathogenic, criteria provided, single submitter	research	Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University	Mar 31, 2020	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 315 of the TARDBP protein (p.Ala315Thr). This variant is present in population databases (rs80356726, gnomAD 0.0009%). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 18288693, 20031275, 25681989, 29411640). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5236). 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: 19833869, 21666678, 23721326, 28334913). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.97

M_CAP

Benign

0.053

MutationTaster

Benign

1.0

A;A;A

ClinPred

0.57

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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