1-11022292-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_007375.4(TARDBP):c.883G>C(p.Gly295Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G295S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TARDBP NM_007375.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.13

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]

MASP2 (HGNC:6902): (MBL associated serine protease 2) This gene encodes a member of the peptidase S1 family of serine proteases. The encoded preproprotein is proteolytically processed to generate A and B chains that heterodimerize to form the mature protease. This protease cleaves complement components C2 and C4 in order to generate C3 convertase in the lectin pathway of the complement system. The encoded protease also plays a role in the coagulation cascade through cleavage of prothrombin to form thrombin. Myocardial infarction and acute stroke patients exhibit reduced serum concentrations of the encoded protein. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_007375.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-11022292-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 21485.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, TARDBP
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859
• PP5: Variant 1-11022292-G-C is Pathogenic according to our data. Variant chr1-11022292-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1806944.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}. Variant chr1-11022292-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TARDBP	NM_007375.4	c.883G>C	p.Gly295Arg	missense_variant	6/6	ENST00000240185.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TARDBP	ENST00000240185.8	c.883G>C	p.Gly295Arg	missense_variant	6/6	1	NM_007375.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251168 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Amyotrophic lateral sclerosis type 10;C3150169:TARDBP-related frontotemporal dementia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 05, 2022

This variant disrupts the p.Gly295 amino acid residue in TARDBP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19224587, 19350673, 28335005). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TARDBP function (PMID: 28335005). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 19224587, 20031275, 25913742). This variant is present in population databases (rs80356723, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 295 of the TARDBP protein (p.Gly295Arg). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Benign	21
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.0	N;.;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.020	D;.;.
Sift4G	Uncertain	0.034	D;.;D
Polyphen		0.73	P;P;.
Vest4		0.87
MutPred		0.79		Gain of methylation at G295 (P = 4e-04);Gain of methylation at G295 (P = 4e-04);.;
MVP		0.99
MPC		1.3
ClinPred		0.60	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs80356723; hg19: chr1-11082349;