1-11016868-C-T

Variant names:

• chr1-11016868-C-T
• rs1553159049
• NM_007375.4:c.263C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_007375.4(TARDBP):​c.263C>T​(p.Thr88Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T88R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TARDBP NM_007375.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TARDBP gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 3.7095 (above the threshold of 3.09). Trascript score misZ: 5.3115 (above the threshold of 3.09). GenCC associations: The gene is linked to amyotrophic lateral sclerosis type 10, frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis, inclusion body myositis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1933338).

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.263C>T	p.Thr88Ile	missense	Exon 3 of 6	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.263C>T	p.Thr88Ile	missense	Exon 3 of 6	ENSP00000240185.4	Q13148-1
	TARDBP	ENST00000649624.1		c.263C>T	p.Thr88Ile	missense	Exon 2 of 6	ENSP00000497327.1	A0A0A0N0M3
	TARDBP	ENST00000639083.1	TSL:5	c.263C>T	p.Thr88Ile	missense	Exon 3 of 6	ENSP00000491203.1	Q13148-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.24
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.74	N
PhyloP100		4.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.10
Sift	Benign	0.30	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.097
MutPred		0.25		Loss of ubiquitination at K84 (P = 0.0455)
MVP		0.49
MPC		1.5
ClinPred		0.85	D
GERP RS		5.4
PromoterAI		0.0060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.50
Mutation Taster		=70/30	polymorphism

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: rs1553159049; hg19: chr1-11076925;