rs80356743

Positions:

chr1-11022587-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3

The NM_007375.4(TARDBP):c.1178C>T(p.Ser393Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000695 in 1,439,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S393S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TARDBP
NM_007375.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.18

Variant links:

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]

TARDBP links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a strand (size 6) in uniprot entity TADBP_HUMAN there are 5 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, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TARDBP	NM_007375.4 linkuse as main transcript	c.1178C>T	p.Ser393Leu	missense_variant	6/6	ENST00000240185.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TARDBP	ENST00000240185.8 linkuse as main transcript	c.1178C>T	p.Ser393Leu	missense_variant	6/6	1	NM_007375.4	P1	Q13148-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000867

AC:

AN:

230568

Hom.:

AF XY:

0.00000807

AC XY:

AN XY:

123984

show subpopulations

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:

0.0000385

Gnomad FIN exome

AF:

0.0000487

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1439392

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713750

show subpopulations

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:

0.0000121

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 26, 2022

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 393 of the TARDBP protein (p.Ser393Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 19224587, 19714537, 21830990, 29630989). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

T;T;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.81

.;T;T

M_CAP

Benign

0.081

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

1.1

L;L;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.2

N;.;.

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0090

D;.;.

Sift4G

Benign

0.24

T;.;.

Polyphen

0.80

P;P;.

Vest4

0.89

MutPred

0.72

Loss of glycosylation at S393 (P = 0.0011);Loss of glycosylation at S393 (P = 0.0011);.;

MVP

0.99

MPC

0.82

ClinPred

0.37

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.22

gMVP

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over