1-11022301-G-A

Position:

• chr1-11022301-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_007375.4(TARDBP):​c.892G>A​(p.Gly298Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TARDBP NM_007375.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 6.94

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 14 ACMG points.

• PM1: In a region_of_interest Disordered (size 42) in uniprot entity TADBP_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_007375.4
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78
• PP5: Variant 1-11022301-G-A is Pathogenic according to our data. Variant chr1-11022301-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11022301-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TARDBP	NM_007375.4	c.892G>A	p.Gly298Ser	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	c.892G>A	p.Gly298Ser	missense_variant	6/6	1	NM_007375.4	ENSP00000240185	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251144 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135726

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 Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 10 Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2008	- -
not provided, no classification provided	literature only	GeneReviews	-	Limited evidence of segregation. -
Likely pathogenic, no assertion criteria provided	provider interpretation	Codex Genetics Limited	Feb 28, 2019	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TARDBP function (PMID: 19515851, 20624952, 24477737, 26883171, 27348499, 30442180). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 5232). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 18396105, 20558945, 21857683, 28709720, 30324134, 32166880). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs4884357, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 298 of the TARDBP protein (p.Gly298Ser). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 22, 2018

- -

TARDBP-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 13, 2024

The TARDBP c.892G>A variant is predicted to result in the amino acid substitution p.Gly298Ser. This variant has been reported in several individuals with amyotrophic lateral sclerosis (ALS, Van Deerlin et al. 2008. PubMed ID: 18396105; Nozaki et al. 2010. PubMed ID: 20558945; Pang et al. 2017. PubMed ID: 28709720; Chen et al. 2020. PubMed ID: 32166880) and has been described as a founder variant for ALS in the Southern Chinese population (Xu et al. 2022. PubMed ID: 35932023). Immunohistochemistry studies from patients' CNS tissues revealed TDP-43 immunopositive inclusions (Van Deerlin et al. 2008. PubMed ID: 18396105), and additional in vitro functional studies using human motor neurons derived from iPS cells have demonstrated that expression of this variant impairs axonal transportation of cytoplasmic granules to distal neuronal compartments (Alami et al. 2014. PubMed ID: 24507191). This variant is located within the conserved C-terminal region of TARDBP, where missense change is not expected to be tolerated and is considered a hot spot for ALS-causing variants (Tiloca et al. 2022. PubMed ID: 36247987). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD and has been consistently classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/5232/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;T;T
Eigen	Benign	0.095
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.52	N;.;.
REVEL	Uncertain	0.49
Sift	Benign	0.28	T;.;.
Sift4G	Benign	0.11	T;.;T
Polyphen		0.063	B;B;.
Vest4		0.90
MutPred		0.76		Gain of glycosylation at G298 (P = 0.0453);Gain of glycosylation at G298 (P = 0.0453);.;
MVP		0.98
MPC		0.94
ClinPred		0.66	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.85

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: rs4884357; hg19: chr1-11082358;