rs80356718

Variant names:

• chr1-11022209-A-G
• rs80356718
• NM_007375.4:c.800A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PP2 PP5 BP4 BS1_Supporting BS2

The NM_007375.4(TARDBP):​c.800A>G​(p.Asn267Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: TARDBP NM_007375.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3 O:1
• Conservation: PhyloP100: 3.44
• Publications: 41 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_benign. The variant received -4 ACMG points.

• 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, amyotrophic lateral sclerosis, frontotemporal dementia with motor neuron disease, inclusion body myositis.
• PP5: Variant 1-11022209-A-G is Pathogenic according to our data. Variant chr1-11022209-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21482.
• BP4: Computational evidence support a benign effect (MetaRNN=0.046908468). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000722 (11/152340) while in subpopulation SAS AF = 0.000829 (4/4828). AF 95% confidence interval is 0.000283. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 11 AD gene.

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.800A>G	p.Asn267Ser	missense	Exon 6 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.800A>G	p.Asn267Ser	missense	Exon 6 of 6	ENSP00000240185.4	Q13148-1
	TARDBP	ENST00000649624.1		c.768+32A>G		intron	N/A	ENSP00000497327.1	A0A0A0N0M3
	TARDBP	ENST00000639083.1	TSL:5	c.800A>G	p.Asn267Ser	missense	Exon 6 of 6	ENSP00000491203.1	Q13148-1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000757 AC: 19 AN: 251128 AF XY: 0.0000663

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000616 AC: 90 AN: 1461666 Hom.: 0 Cov.: 31 AF XY: 0.0000619 AC XY: 45 AN XY: 727144

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.000112 AC: 5 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5762

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111836

Other (OTH) AF: 0.0000497 AC: 3 AN: 60378

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74494

African (AFR) AF: 0.00 AC: 0 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.0000668 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Amyotrophic lateral sclerosis type 10 (3)
-	1	-	Amyotrophic lateral sclerosis type 10;C3150169:FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, TARDBP-RELATED (1)
1	-	-	FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, TARDBP-RELATED (1)
-	1	-	Inborn genetic diseases (1)
1	-	-	not provided (1)
1	-	-	TARDBP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.18
Sift	Benign	0.27	T
Sift4G	Benign	0.37	T
Polyphen		0.0070	B
Vest4		0.18
MVP		0.74
MPC		0.73
ClinPred		0.058	T
GERP RS		2.2
PromoterAI		0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.59
Mutation Taster		=19/81	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs80356718; hg19: chr1-11082266;