1-11022301-G-A

Variant names:

• chr1-11022301-G-A
• rs4884357
• NM_007375.4:c.892G>A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G298V) has been classified as Likely 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 16 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 chr1-11022302-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 873205.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• 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, 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 rank	MANE	Protein	UniProt
TARDBP	NM_007375.4	c.892G>A	p.Gly298Ser	missense_variant	Exon 6 of 6	ENST00000240185.8	NP_031401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TARDBP	ENST00000240185.8	c.892G>A	p.Gly298Ser	missense_variant	Exon 6 of 6	1	NM_007375.4	ENSP00000240185.4
TARDBP	ENST00000649624.1	c.768+124G>A		intron_variant	Intron 5 of 5			ENSP00000497327.1

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

May 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Limited evidence of segregation. -

Feb 28, 2019

Codex Genetics Limited

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

not provided Pathogenic:1

Jun 22, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TARDBP-related disorder Pathogenic:1

May 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Amyotrophic lateral sclerosis type 10;C3150169:FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, TARDBP-RELATED Pathogenic:1

Mar 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is present in population databases (rs4884357, gnomAD 0.0009%). 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. ClinVar contains an entry for this variant (Variation ID: 5232). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TARDBP function (PMID: 19515851, 20624952, 24477737, 26883171, 27348499, 30442180). For these reasons, this variant has been classified 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;.
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;