rs565091566

Variant names:

• chr1-11013763-C-A
• NM_007375.4:c.36C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-11013763-C-A
• chr1-11013763-C-T

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.36C>A​(p.Asn12Lys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N12N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TARDBP NM_007375.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.29

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=0.23328623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TARDBP	NM_007375.4	c.36C>A	p.Asn12Lys	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.36C>A	p.Asn12Lys	missense_variant	Exon 2 of 6	1	NM_007375.4	ENSP00000240185.4
TARDBP	ENST00000649624.1	c.36C>A	p.Asn12Lys	missense_variant	Exon 1 of 6			ENSP00000497327.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1460272 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726338

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.71	.;D;D;T;T;T;T;.;T;T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.81	T;.;T;.;T;T;T;T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.5	.;M;M;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.8	.;D;.;.;.;.;D;.;.;.;.
REVEL	Benign	0.24
Sift	Benign	0.11	.;T;.;.;.;.;T;.;.;.;.
Sift4G	Benign	0.14	T;T;.;T;T;T;T;.;.;T;T
Polyphen		0.95	.;P;P;.;.;.;.;.;.;.;.
Vest4		0.44, 0.43, 0.45, 0.41, 0.42
MutPred		0.30		Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);
MVP		0.82
MPC		1.6
ClinPred		0.99	D
GERP RS		-4.3
Varity_R		0.48
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-11073820;