rs80356716

Positions:

• chr1-11013922-T-A
• chr1-11013922-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000240185.8(TARDBP):​c.195T>A​(p.Asp65Glu) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TARDBP ENST00000240185.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.110

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12101361).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TARDBP	NM_007375.4	c.195T>A	p.Asp65Glu	missense_variant	2/6	ENST00000240185.8	NP_031401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TARDBP	ENST00000240185.8	c.195T>A	p.Asp65Glu	missense_variant	2/6	1	NM_007375.4	ENSP00000240185	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	12
DANN	Benign	0.84
DEOGEN2	Benign	0.23	.;T;T;T;T;T;T;.;T;T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.80	T;.;T;.;T;T;T;T;T;T;T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	-0.19	.;N;N;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.79	N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.78	.;N;.;.;.;.;N;.;.;.;.
REVEL	Benign	0.11
Sift	Benign	1.0	.;T;.;.;.;.;T;.;.;.;.
Sift4G	Benign	0.86	T;T;.;T;T;T;T;.;.;T;T
Polyphen		0.0010	.;B;B;.;.;.;.;.;.;.;.
Vest4		0.13, 0.066, 0.056, 0.069, 0.070
MutPred		0.41		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.41
MPC		1.3
ClinPred		0.48	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.15
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs80356716; hg19: chr1-11073979;