chr1-11013925-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_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. In-silico tool predicts a benign outcome for this variant. 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

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

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 545 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TARDBP	NM_007375.4 link	c.198T>C	p.Ala66Ala	synonymous_variant	Exon 2 of 6	ENST00000240185.8	NP_031401.1	Q13148-1Q9H256A0A024R4E2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TARDBP	ENST00000240185.8 link	c.198T>C	p.Ala66Ala	synonymous_variant	Exon 2 of 6	1	NM_007375.4	ENSP00000240185.4		Q13148-1
TARDBP	ENST00000649624.1 link	c.198T>C	p.Ala66Ala	synonymous_variant	Exon 1 of 6			ENSP00000497327.1		A0A0A0N0M3

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

GnomAD3 exomes

AF:

0.00670

AC:

1685

AN:

251494

Hom.:

AF XY:

0.00746

AC XY:

1014

AN XY:

135922

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 SAS exome

AF:

0.0191

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

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00201

Gnomad4 ASJ exome

AF:

0.0567

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0191

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.00185

Gnomad4 OTH exome

AF:

0.00737

GnomAD4 genome

AF:

0.00358

AC:

545

AN:

152320

Hom.:

Cov.:

AF XY:

0.00395

AC XY:

294

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00262

Gnomad4 ASJ

AF:

0.0519

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0207

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00244

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00688

Hom.:

Bravo

AF:

0.00352

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.00518

EpiControl

AF:

0.00474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Jan 09, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18545701, 25588603) -

Sep 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TARDBP: BP4, BP7, BS1, BS2 -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Amyotrophic lateral sclerosis type 10

Benign:5

Jun 28, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Dec 29, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Jul 25, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

May 19, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Amyotrophic lateral sclerosis type 10;C3150169:TARDBP-related frontotemporal dementia

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

8.5

DANN

Uncertain

0.98

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over