1-11013922-T-G

Variant names:

• chr1-11013922-T-G
• rs80356716
• NM_007375.4:c.195T>G

Variant summary

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

The NM_007375.4(TARDBP):​c.195T>G​(p.Asp65Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,316 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: TARDBP NM_007375.4 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 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11860338).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TARDBP	NM_007375.4	c.195T>G	p.Asp65Glu	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.195T>G	p.Asp65Glu	missense_variant	Exon 2 of 6	1	NM_007375.4	ENSP00000240185.4
TARDBP	ENST00000649624.1	c.195T>G	p.Asp65Glu	missense_variant	Exon 1 of 6			ENSP00000497327.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74488

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.82
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	0.64	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;.;.;.;.;.;.;.;.
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
Varity_R		0.15
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;