1-11013925-T-C

Position:

• chr1-11013925-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.890

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
TARDBP	NM_007375.4	c.198T>C	p.Ala66Ala	synonymous_variant	2/6	ENST00000240185.8	NP_031401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TARDBP	ENST00000240185.8	c.198T>C	p.Ala66Ala	synonymous_variant	2/6	1	NM_007375.4	ENSP00000240185.4
TARDBP	ENST00000649624.1	c.198T>C	p.Ala66Ala	synonymous_variant	1/6			ENSP00000497327.1

Frequencies

GnomAD3 genomes AF: 0.00358 AC: 545 AN: 152202 Hom.: 12 Cov.: 33

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.: 36 AF XY: 0.00746 AC XY: 1014 AN XY: 135922

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.: 31 AF XY: 0.00455 AC XY: 3310 AN XY: 727248

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.: 12 Cov.: 33 AF XY: 0.00395 AC XY: 294 AN XY: 74490

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.: 7

Bravo AF: 0.00352

Asia WGS AF: 0.00693 AC: 24 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

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2020	This variant is associated with the following publications: (PMID: 18545701, 25588603) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TARDBP: BP4, BP7, BS1, BS2 -

Amyotrophic lateral sclerosis type 10 Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Dec 29, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 25, 2017

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 2022

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

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

Other links and lift over

dbSNP: rs61730366; hg19: chr1-11073982;