1-11022290-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PM1PM2PM5PP2BS2

The NM_007375.4(TARDBP):ā€‹c.881G>Cā€‹(p.Gly294Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G294V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

TARDBP
NM_007375.4 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 4.63
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a region_of_interest Disordered (size 42) in uniprot entity TADBP_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) 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 chr1-11022290-G-T 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.
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TARDBPNM_007375.4 linkuse as main transcriptc.881G>C p.Gly294Ala missense_variant 6/6 ENST00000240185.8 NP_031401.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TARDBPENST00000240185.8 linkuse as main transcriptc.881G>C p.Gly294Ala missense_variant 6/61 NM_007375.4 ENSP00000240185 P1Q13148-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461670
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727144
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 10 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 2009- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 16, 2022The p.G294A variant (also known as c.881G>C), located in coding exon 5 of the TARDBP gene, results from a G to C substitution at nucleotide position 881. The glycine at codon 294 is replaced by alanine, an amino acid with similar properties. This alteration has been detected in an individual with sporadic, late-onset amyotrophic lateral sclerosis (Sreedharan J et al. Science, 2008 Mar;319:1668-72). This amino acid position is well conserved in available vertebrate species; however, alanine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.27
CADD
Benign
18
DANN
Benign
0.96
DEOGEN2
Uncertain
0.50
D;D;T
Eigen
Benign
-0.021
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.91
.;D;D
M_CAP
Benign
0.061
D
MetaRNN
Uncertain
0.56
D;D;D
MetaSVM
Uncertain
-0.13
T
MutationAssessor
Benign
1.7
L;L;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-0.56
N;.;.
REVEL
Uncertain
0.51
Sift
Benign
0.58
T;.;.
Sift4G
Benign
0.30
T;.;D
Polyphen
0.028
B;B;.
Vest4
0.36
MutPred
0.78
Loss of phosphorylation at S292 (P = 0.1921);Loss of phosphorylation at S292 (P = 0.1921);.;
MVP
1.0
MPC
1.0
ClinPred
0.31
T
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.46
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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.

Other links and lift over

dbSNP: rs80356721; hg19: chr1-11082347; API