rs752580444

Variant names:

• chr1-11013822-C-G
• rs752580444
• NM_007375.4:c.95C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-11013822-C-G
• chr1-11013822-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_007375.4(TARDBP):​c.95C>G​(p.Thr32Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T32I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TARDBP NM_007375.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TARDBP gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 3.7095 (above the threshold of 3.09). Trascript score misZ: 5.3115 (above the threshold of 3.09). GenCC associations: The gene is linked to amyotrophic lateral sclerosis type 10, amyotrophic lateral sclerosis, frontotemporal dementia with motor neuron disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TARDBP	NM_007375.4	c.95C>G	p.Thr32Arg	missense_variant	Exon 2 of 6	ENST00000240185.8	NP_031401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TARDBP	ENST00000240185.8	c.95C>G	p.Thr32Arg	missense_variant	Exon 2 of 6	1	NM_007375.4	ENSP00000240185.4
TARDBP	ENST00000649624.1	c.95C>G	p.Thr32Arg	missense_variant	Exon 1 of 6			ENSP00000497327.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	.;D;D;T;T;T;T;.;T;T;T
Eigen	Benign	0.025
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;.;D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.6	.;M;M;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.1	.;N;.;.;.;.;N;.;.;.;.
REVEL	Uncertain	0.53
Sift	Benign	0.17	.;T;.;.;.;.;T;.;.;.;.
Sift4G	Benign	0.18	T;T;.;T;T;T;T;.;.;T;T
Polyphen		0.066	.;B;B;.;.;.;.;.;.;.;.
Vest4		0.54, 0.55, 0.54, 0.54, 0.56
MutPred		0.70		Gain of methylation at T32 (P = 0.044);Gain of methylation at T32 (P = 0.044);Gain of methylation at T32 (P = 0.044);Gain of methylation at T32 (P = 0.044);Gain of methylation at T32 (P = 0.044);Gain of methylation at T32 (P = 0.044);Gain of methylation at T32 (P = 0.044);Gain of methylation at T32 (P = 0.044);Gain of methylation at T32 (P = 0.044);Gain of methylation at T32 (P = 0.044);Gain of methylation at T32 (P = 0.044);
MVP		0.78
MPC		1.6
ClinPred		0.95	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.49		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs752580444; hg19: chr1-11073879;