rs80356734

Positions:

• chr1-11022464-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 15P and 1B. PM1 PM2 PM5 PP2 PP5_Very_Strong BP4

The NM_007375.4(TARDBP):​c.1055A>G​(p.Asn352Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. N352D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (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: 3.83

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 hotspot region, there are 3 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 chr1-11022464-A-C is described in Lovd as [Pathogenic].
• 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.
• PP5: Variant 1-11022464-A-G is Pathogenic according to our data. Variant chr1-11022464-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11022464-A-G is described in Lovd as [Pathogenic]. Variant chr1-11022464-A-G is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.30383795). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TARDBP	NM_007375.4	c.1055A>G	p.Asn352Ser	missense_variant	6/6	ENST00000240185.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TARDBP	ENST00000240185.8	c.1055A>G	p.Asn352Ser	missense_variant	6/6	1	NM_007375.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458662 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724932

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	TARDBP: PP1:Strong, PM1, PM2, PS4:Moderate, PP2, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 20, 2019	Not found in the total gnomAD dataset, and the data is high quality (0/281796 chr). Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Located in potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism. Statistically associated with disease, but in a single family. (p < 0.05) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Amyotrophic lateral sclerosis type 10 Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 11, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Aug 24, 2022	ACMG criteria used to clasify this variant: PS3, PM2, PS4, PP2 -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 352 of the TARDBP protein (p.Asn352Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 18779421, 23327806, 24117534, 24237396). ClinVar contains an entry for this variant (Variation ID: 21468). 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: 22406069, 24440310). This variant disrupts the p.Asn352 amino acid residue in TARDBP. Other variant(s) that disrupt this residue have been observed in individuals with TARDBP-related conditions (PMID: 20031275), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.32	T;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	.;D;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.20	N;N;.
MutationTaster	Benign	0.99	A;A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.1	N;.;.
REVEL	Benign	0.28
Sift	Benign	0.60	T;.;.
Sift4G	Benign	0.38	T;.;.
Polyphen		0.0	B;B;.
Vest4		0.53
MutPred		0.74		Gain of phosphorylation at N352 (P = 0.033);Gain of phosphorylation at N352 (P = 0.033);.;
MVP		0.83
MPC		0.73
ClinPred		0.68	D
GERP RS		5.8
Varity_R		0.44
gMVP		0.69

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: rs80356734; hg19: chr1-11082521;