rs1553159049

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-11016868-C-G
• chr1-11016868-C-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>G​(p.Thr88Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. T88I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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=0.17809075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TARDBP	NM_007375.4	c.263C>G	p.Thr88Arg	missense_variant	Exon 3 of 6	ENST00000240185.8	NP_031401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TARDBP	ENST00000240185.8	c.263C>G	p.Thr88Arg	missense_variant	Exon 3 of 6	1	NM_007375.4	ENSP00000240185.4
TARDBP	ENST00000649624.1	c.263C>G	p.Thr88Arg	missense_variant	Exon 2 of 6			ENSP00000497327.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 21, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T88R variant (also known as c.263C>G), located in coding exon 2 of the TARDBP gene, results from a C to G substitution at nucleotide position 263. The threonine at codon 88 is replaced by arginine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	.;T;T;T;T;T;T;T;T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	0.024
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;.;D;.;T;D;D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.8	.;L;L;.;.;.;.;.;.;.
PhyloP100		4.5
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.89	.;N;.;.;.;.;N;.;.;.
REVEL	Benign	0.11
Sift	Benign	0.53	.;T;.;.;.;.;T;.;.;.
Sift4G	Benign	0.44	T;T;.;T;T;T;T;.;T;T
Polyphen		0.014	.;B;B;.;.;.;.;.;.;.
Vest4		0.28, 0.28, 0.28, 0.28
MutPred		0.29		Gain of MoRF binding (P = 0.0104);Gain of MoRF binding (P = 0.0104);Gain of MoRF binding (P = 0.0104);Gain of MoRF binding (P = 0.0104);.;Gain of MoRF binding (P = 0.0104);Gain of MoRF binding (P = 0.0104);Gain of MoRF binding (P = 0.0104);Gain of MoRF binding (P = 0.0104);Gain of MoRF binding (P = 0.0104);
MVP		0.64
MPC		1.6
ClinPred		0.43	T
GERP RS		5.4
PromoterAI		0.0012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.74
Mutation Taster		=42/58	disease causing

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;