rs367543041

chr1-11022553-G-Achr1-11022553-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 15P and 4B. PM1 PM2 PM5 PP2 PP5_Very_Strong BS2

The NM_007375.4(TARDBP):c.1144G>A(p.Ala382Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,428,682 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A382P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TARDBP NM_007375.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 2.95

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr1-11022553-G-C is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, TARDBP
• PP5: Variant 1-11022553-G-A is Pathogenic according to our data. Variant chr1-11022553-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11022553-G-A is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAdExome at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TARDBP	NM_007375.4	c.1144G>A	p.Ala382Thr	missense_variant	6/6	ENST00000240185.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TARDBP	ENST00000240185.8	c.1144G>A	p.Ala382Thr	missense_variant	6/6	1	NM_007375.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000304 AC: 7 AN: 230196 Hom.: 0 AF XY: 0.0000242 AC XY: 3 AN XY: 123896

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: 0.0000662

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1428682 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2 AN XY: 706410

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: 0.00000274

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 10 Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	research	Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University	Mar 31, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	Identified in both FALS and SALS. Familial and simplex cases share founder haplotype. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2011	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	TARDBP: PP1:Strong, PM1, PM2, PS4:Moderate, PP2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2016	The A382T variant in the TARDBP gene was originally reported as a pathogenic variant in two French individuals with personal and family histories of amyotrophic sclerosis (ALS) (Kabashi et al., 2008). This variant has since been reported in association with both familial and sporadic ALS and has also been identified in individuals with frontotemporal lobe dementia with or without motor neuron disease (Chio et al., 2010; Chio et al., 2011; Quadei et al., 2011). In addition, the A382T variant has been reported in individuals with a clinical diagnosis of Parkinson disease (Quadri et al., 2011). Although the precise disease mechanism is unclear, functional studies indicate that expression of the A382T variant protein results in cellular toxicity of motor neurons (Kabashi et al., 2010; Watanabe et al., 2013). Missense variants in nearby residues (N378D, N378S, S379P, S379C, A382P, I383V, G384R, W385G, N390D) have been reported in the Human Gene Mutation Database in association with amyotrophic lateral sclerosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. The A382T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A382T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. The A382T variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Amyotrophic lateral sclerosis type 10;C3150169:TARDBP-related frontotemporal dementia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 11, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 382 of the TARDBP protein (p.Ala382Thr). This variant is present in population databases (rs367543041, gnomAD 0.008%). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 21220647, 21651514, 25792239, 32951934). ClinVar contains an entry for this variant (Variation ID: 21474). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects TARDBP function (PMID: 19959528). For these reasons, this variant has been classified as Pathogenic. -

FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, TARDBP-RELATED Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2011

- -

TARDBP-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 08, 2024

The TARDBP c.1144G>A variant is predicted to result in the amino acid substitution p.Ala382Thr. This variant has previously been reported to be causative for amyotrophic lateral sclerosis and/or frontotemporal dementia (Kabashi et al. 2008. PubMed ID: 18372902; Chiò et al. 2010. PubMed ID: 20697052; Corrado et al. 2009. PubMed ID: 19224587). This variant is reported in 0.0066% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant also resides in mutational hotspot for pathogenic missense changes and has been classified as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/21474/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.76	N;.;.
REVEL	Uncertain	0.52
Sift	Benign	0.12	T;.;.
Sift4G	Benign	0.62	T;.;.
Polyphen		0.27	B;B;.
Vest4		0.36
MutPred		0.75		Gain of glycosylation at A382 (P = 0.0055);Gain of glycosylation at A382 (P = 0.0055);.;
MVP		0.98
MPC		0.91
ClinPred		0.042	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.075
gMVP		0.77

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

Other links and lift over

dbSNP: rs367543041; hg19: chr1-11082610;