rs80356732

Positions:

• chr1-11022444-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PP2 PP5_Moderate BP4

The NM_007375.4(TARDBP):​c.1035C>A​(p.Asn345Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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, single submitter P:1
• Conservation: PhyloP100: 0.107

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain 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.
• PP5: Variant 1-11022444-C-A is Pathogenic according to our data. Variant chr1-11022444-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 21467.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-11022444-C-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.33259726). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TARDBP	NM_007375.4	c.1035C>A	p.Asn345Lys	missense_variant	6/6	ENST00000240185.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TARDBP	ENST00000240185.8	c.1035C>A	p.Asn345Lys	missense_variant	6/6	1	NM_007375.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250832 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135538

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 07, 2022

This missense change has been observed in individuals with familial amyotrophic lateral sclerosis (PMID: 18802454, 20031275, 31124595; Invitae). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TARDBP function (PMID: 19465477, 22406069). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TARDBP protein function. ClinVar contains an entry for this variant (Variation ID: 21467). This variant is present in population databases (rs80356732, gnomAD 0.002%). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 345 of the TARDBP protein (p.Asn345Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.50	T;T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.28	T
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.6	N;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.25	T;.;.
Sift4G	Benign	0.92	T;.;.
Polyphen		0.041	B;B;.
Vest4		0.61
MutPred		0.76		Gain of ubiquitination at N345 (P = 0.0077);Gain of ubiquitination at N345 (P = 0.0077);.;
MVP		0.80
MPC		1.2
ClinPred		0.11	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.93

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: rs80356732; hg19: chr1-11082501;