rs80356730

Variant names:

• chr1-11022418-A-G
• rs80356730
• NM_007375.4:c.1009A>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_007375.4(TARDBP):​c.1009A>G​(p.Met337Val) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 8.95
• Publications: 467 publications found

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]

MASP2 Gene-Disease associations (from GenCC):

• immunodeficiency due to MASP-2 deficiency

  Inheritance: AR Classification: STRONG Submitted by: Laboratory for Molecular Medicine

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_007375.4
• PM2: Very rare variant in population databases, with high coverage
• 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, frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis, inclusion body myositis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864
• PP5: Variant 1-11022418-A-G is Pathogenic according to our data. Variant chr1-11022418-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 5228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TARDBP	NM_007375.4	c.1009A>G	p.Met337Val	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.1009A>G	p.Met337Val	missense_variant	Exon 6 of 6	1	NM_007375.4	ENSP00000240185.4
TARDBP	ENST00000649624.1	c.768+241A>G		intron_variant	Intron 5 of 5			ENSP00000497327.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251022 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000262 Hom.: 0

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

Mar 15, 2023

Department of Neurology-Cell Therapy Center, Hanyang University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Met337Val variant in TARDBP has been reported in Western countries and Asia with autosomal dominant amyotrophic lateral sclerosis, segregated with the disease in over 10 affected relatives (Sreedharan 2008, Kirby 2010, Tamaoka 2010, Xu 2018), and was absent from large population studies. Additionally, studies indicate that the Met337Var variant transgenic mouse presented worsened dose-dependent disease phenotype in terms of motor dysfunction, neurodegeneration, gliosis, and development of ubiquitin and phosphorylated TDP-43 pathology (Janssens 2013). In summary, the Met337Val variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and functional evidence. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Convincing evidence of segregation. -

Mar 21, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 337 of the TARDBP protein (p.Met337Val). This variant is present in population databases (rs80356730, gnomAD 0.002%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (ALS) (PMID: 18309045, 20154440, 28430856, 28709720). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5228). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 18309045, 19465477, 20600671, 23401527, 23827948, 24143176, 24507191). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	.;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.1	M;M;.
PhyloP100		8.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.12	N;.;.
REVEL	Pathogenic	0.70
Sift	Benign	0.18	T;.;.
Sift4G	Benign	0.63	T;.;.
Polyphen		0.64	P;P;.
Vest4		0.89
MutPred		0.80		Gain of MoRF binding (P = 0.0865);Gain of MoRF binding (P = 0.0865);.;
MVP		0.98
MPC		0.95
ClinPred		0.37	T
GERP RS		5.8
PromoterAI		-0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.98
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80356730; hg19: chr1-11082475;