1-11019020-A-G

Variant names:

• chr1-11019020-A-G
• rs2273348
• NM_007375.4:c.543+147A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 20 publications found

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]

TARDBP Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Genomics England PanelApp
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• frontotemporal dementia with motor neuron disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• inclusion body myositis

  Inheritance: AD Classification: LIMITED Submitted by: Broad Center for Mendelian Genomics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1293144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007375.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TARDBP	NM_007375.4	MANE Select	c.543+147A>G		intron	N/A	NP_031401.1	Q13148-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TARDBP	ENST00000240185.8	TSL:1 MANE Select	c.543+147A>G		intron	N/A	ENSP00000240185.4	Q13148-1
	TARDBP	ENST00000649624.1		c.543+147A>G		intron	N/A	ENSP00000497327.1	A0A0A0N0M3
	TARDBP	ENST00000639083.1	TSL:5	c.543+147A>G		intron	N/A	ENSP00000491203.1	Q13148-1

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

African (AFR) AF: 0.244 AC: 5068 AN: 20766

American (AMR) AF: 0.795 AC: 30749 AN: 38660

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 15151 AN: 21848

East Asian (EAS) AF: 0.681 AC: 24235 AN: 35570

South Asian (SAS) AF: 0.701 AC: 49421 AN: 70486

European-Finnish (FIN) AF: 0.824 AC: 38879 AN: 47204

Middle Eastern (MID) AF: 0.706 AC: 3004 AN: 4256

European-Non Finnish (NFE) AF: 0.818 AC: 451815 AN: 552078

Other (OTH) AF: 0.749 AC: 29599 AN: 39506

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

African (AFR) AF: 0.259 AC: 10742 AN: 41500

American (AMR) AF: 0.727 AC: 11117 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 2397 AN: 3472

East Asian (EAS) AF: 0.657 AC: 3400 AN: 5172

South Asian (SAS) AF: 0.694 AC: 3343 AN: 4820

European-Finnish (FIN) AF: 0.816 AC: 8638 AN: 10582

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.812 AC: 55221 AN: 67994

Other (OTH) AF: 0.684 AC: 1439 AN: 2104

Alfa AF: 0.754 Hom.: 150601

Bravo AF: 0.619

Asia WGS AF: 0.651 AC: 2263 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.31
PhyloP100		0.16
PromoterAI		0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2273348; hg19: chr1-11079077;