rs797044594

Variant names:

• chr1-11022559-G-C
• rs797044594
• NM_007375.4:c.1150G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-11022559-G-C
• chr1-11022559-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_007375.4(TARDBP):​c.1150G>C​(p.Gly384Arg) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• 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 O:1
• Conservation: PhyloP100: 7.20
• Publications: 8 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]

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]

MASP2 Gene-Disease associations (from GenCC):

• immunodeficiency due to MASP-2 deficiency

  Inheritance: AR Classification: STRONG Submitted by: Laboratory for Molecular Medicine

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_007375.4
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787
• PP5: Variant 1-11022559-G-C is Pathogenic according to our data. Variant chr1-11022559-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190399.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TARDBP	NM_007375.4	c.1150G>C	p.Gly384Arg	missense_variant	Exon 6 of 6	ENST00000240185.8	NP_031401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TARDBP	ENST00000240185.8	c.1150G>C	p.Gly384Arg	missense_variant	Exon 6 of 6	1	NM_007375.4	ENSP00000240185.4
TARDBP	ENST00000649624.1	c.768+382G>C		intron_variant	Intron 5 of 5			ENSP00000497327.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

May 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 190399). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 20031275, 20577002, 21438137, 28444446; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 384 of the TARDBP protein (p.Gly384Arg). -

not provided Uncertain:1

May 15, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Amyotrophic lateral sclerosis type 10 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Limited evidence of segregation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.1	M;M;.
PhyloP100		7.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.9	D;.;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.010	D;.;.
Polyphen		0.96	D;D;.
Vest4		0.96
MutPred		0.60		Gain of MoRF binding (P = 0.0054);Gain of MoRF binding (P = 0.0054);.;
MVP		0.98
MPC		2.2
ClinPred		0.97	D
GERP RS		4.6
PromoterAI		-0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.60
gMVP		0.92
Mutation Taster		=7/93	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: rs797044594; hg19: chr1-11082616;