rs2273348

Positions:

• chr1-11019020-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007375.4(TARDBP):​c.543+147A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.758 in 982,510 control chromosomes in the GnomAD database, including 293,039 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (35502 hom., cov: 33)
  • Exomes 𝑓: 0.78 (257537 hom.)
• Consequence: TARDBP NM_007375.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.164

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-11019020-A-G is Benign according to our data. Variant chr1-11019020-A-G is described in ClinVar as [Benign]. Clinvar id is 1293144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11019020-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TARDBP	NM_007375.4	c.543+147A>G		intron_variant		ENST00000240185.8	NP_031401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TARDBP	ENST00000240185.8	c.543+147A>G		intron_variant		1	NM_007375.4	ENSP00000240185	P1

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97261 AN: 152016 Hom.: 35491 Cov.: 33

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.868

Gnomad AMR AF: 0.727

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.657

Gnomad SAS AF: 0.693

Gnomad FIN AF: 0.816

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.812

Gnomad OTH AF: 0.682

GnomAD4 exome AF: 0.780 AC: 647921 AN: 830374 Hom.: 257537 Cov.: 11 AF XY: 0.778 AC XY: 338175 AN XY: 434530

Gnomad4 AFR exome AF: 0.244

Gnomad4 AMR exome AF: 0.795

Gnomad4 ASJ exome AF: 0.693

Gnomad4 EAS exome AF: 0.681

Gnomad4 SAS exome AF: 0.701

Gnomad4 FIN exome AF: 0.824

Gnomad4 NFE exome AF: 0.818

Gnomad4 OTH exome AF: 0.749

GnomAD4 genome AF: 0.640 AC: 97303 AN: 152136 Hom.: 35502 Cov.: 33 AF XY: 0.641 AC XY: 47641 AN XY: 74378

Gnomad4 AFR AF: 0.259

Gnomad4 AMR AF: 0.727

Gnomad4 ASJ AF: 0.690

Gnomad4 EAS AF: 0.657

Gnomad4 SAS AF: 0.694

Gnomad4 FIN AF: 0.816

Gnomad4 NFE AF: 0.812

Gnomad4 OTH AF: 0.684

Alfa AF: 0.781 Hom.: 63068

Bravo AF: 0.619

Asia WGS AF: 0.651 AC: 2263 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

LitVar

Other links and lift over

dbSNP: rs2273348; hg19: chr1-11079077;