1-11013758-G-A

Position:

• chr1-11013758-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_007375.4(TARDBP):​c.31G>A​(p.Glu11Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TARDBP NM_007375.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.70

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TARDBP. . Gene score misZ 3.7095 (greater than the threshold 3.09). Trascript score misZ 5.3115 (greater than threshold 3.09). GenCC has associacion of gene with amyotrophic lateral sclerosis type 10, amyotrophic lateral sclerosis, frontotemporal dementia with motor neuron disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TARDBP	NM_007375.4	c.31G>A	p.Glu11Lys	missense_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.31G>A	p.Glu11Lys	missense_variant	2/6	1	NM_007375.4	ENSP00000240185.4
TARDBP	ENST00000649624.1	c.31G>A	p.Glu11Lys	missense_variant	1/6			ENSP00000497327.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2024

The c.31G>A (p.E11K) alteration is located in exon 2 (coding exon 1) of the TARDBP gene. This alteration results from a G to A substitution at nucleotide position 31, causing the glutamic acid (E) at amino acid position 11 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	.;D;D;T;T;T;T;.;T;T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;.;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.6	.;M;M;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.7	.;D;.;.;.;.;D;.;.;.;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.0030	.;D;.;.;.;.;D;.;.;.;.
Sift4G	Uncertain	0.011	D;D;.;D;D;D;D;.;.;D;D
Polyphen		0.93	.;P;P;.;.;.;.;.;.;.;.
Vest4		0.64, 0.80, 0.80, 0.79, 0.78
MutPred		0.30		Gain of ubiquitination at E11 (P = 0.0039);Gain of ubiquitination at E11 (P = 0.0039);Gain of ubiquitination at E11 (P = 0.0039);Gain of ubiquitination at E11 (P = 0.0039);Gain of ubiquitination at E11 (P = 0.0039);Gain of ubiquitination at E11 (P = 0.0039);Gain of ubiquitination at E11 (P = 0.0039);Gain of ubiquitination at E11 (P = 0.0039);Gain of ubiquitination at E11 (P = 0.0039);Gain of ubiquitination at E11 (P = 0.0039);Gain of ubiquitination at E11 (P = 0.0039);
MVP		0.92
MPC		2.4
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.86
gMVP		1.0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-11073815;