1-11013925-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_StrongBP7BS1BS2

The NM_007375.4(TARDBP):c.198T>C(p.Ala66Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,614,210 control chromosomes in the GnomAD database, including 115 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 12 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 103 hom. )

Consequence

TARDBP
NM_007375.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.890

Publications

19 publications found

Variant links:

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

TARDBP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP6

Variant 1-11013925-T-C is Benign according to our data. Variant chr1-11013925-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 291734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.89 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00358 (545/152320) while in subpopulation SAS AF = 0.0207 (100/4832). AF 95% confidence interval is 0.0174. There are 12 homozygotes in GnomAd4. There are 294 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 545 AD gene.

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.198T>C	p.Ala66Ala	synonymous	Exon 2 of 6	NP_031401.1	Q13148-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TARDBP	ENST00000240185.8	TSL:1 MANE Select	c.198T>C	p.Ala66Ala	synonymous	Exon 2 of 6	ENSP00000240185.4	Q13148-1
TARDBP	ENST00000649624.1		c.198T>C	p.Ala66Ala	synonymous	Exon 1 of 6	ENSP00000497327.1	A0A0A0N0M3
TARDBP	ENST00000639083.1	TSL:5	c.198T>C	p.Ala66Ala	synonymous	Exon 2 of 6	ENSP00000491203.1	Q13148-1

Frequencies

GnomAD3 genomes

AF:

0.00358

AC:

545

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.0519

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00244

Gnomad OTH

AF:

0.00575

GnomAD2 exomes

AF:

0.00670

AC:

1685

AN:

251494

AF XY:

0.00746

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.0584

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00336

Gnomad OTH exome

AF:

0.00798

GnomAD4 exome

AF:

0.00399

AC:

5832

AN:

1461890

Hom.:

103

Cov.:

AF XY:

0.00455

AC XY:

3310

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

33480

American (AMR)

AF:

0.00201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0567

AC:

1481

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0191

AC:

1645

AN:

86258

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0142

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00185

AC:

2056

AN:

1112008

Other (OTH)

AF:

0.00737

AC:

445

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

389

778

1166

1555

1944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00358

AC:

545

AN:

152320

Hom.:

Cov.:

AF XY:

0.00395

AC XY:

294

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41584

American (AMR)

AF:

0.00262

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0519

AC:

180

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.0207

AC:

100

AN:

4832

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00244

AC:

166

AN:

68024

Other (OTH)

AF:

0.00569

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00647

Hom.:

Bravo

AF:

0.00352

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.00518

EpiControl

AF:

0.00474

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Amyotrophic lateral sclerosis type 10 (5)

not provided (5)

Amyotrophic lateral sclerosis type 10;C3150169:FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, TARDBP-RELATED (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

8.5

(source)

DANN

Uncertain

0.98

PhyloP100

-0.89

PromoterAI

0.0012

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over