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NM_001065.4(TNFRSF1A):c.625+10A>G AND Multiple sclerosis, susceptibility to, 5

Germline classification:
risk factor (1 submission)
Last evaluated:
Aug 23, 2012
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000030698.13

Allele description [Variation Report for NM_001065.4(TNFRSF1A):c.625+10A>G]

NM_001065.4(TNFRSF1A):c.625+10A>G

Gene:
TNFRSF1A:TNF receptor superfamily member 1A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12p13.31
Genomic location:
Preferred name:
NM_001065.4(TNFRSF1A):c.625+10A>G
HGVS:
  • NC_000012.12:g.6330843T>C
  • NG_007506.1:g.16253A>G
  • NM_001065.4:c.625+10A>GMANE SELECT
  • NM_001346091.2:c.301+10A>G
  • NM_001346092.2:c.166+10A>G
  • LRG_193t1:c.625+10A>G
  • LRG_193:g.16253A>G
  • NC_000012.11:g.6440009T>C
  • NM_001065.3:c.625+10A>G
Nucleotide change:
IVS6, A-G (rs1800693)
Links:
OMIM: 191190.0013; dbSNP: rs1800693
NCBI 1000 Genomes Browser:
rs1800693
Molecular consequence:
  • NM_001065.4:c.625+10A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001346091.2:c.301+10A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001346092.2:c.166+10A>G - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
Multiple sclerosis, susceptibility to, 5 (MS5)
Identifiers:
MONDO: MONDO:0013893; MedGen: C3553728; OMIM: 614810

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000053359OMIM
no assertion criteria provided
risk factor
(Aug 23, 2012)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis.

Gregory AP, Dendrou CA, Attfield KE, Haghikia A, Xifara DK, Butter F, Poschmann G, Kaur G, Lambert L, Leach OA, Prömel S, Punwani D, Felce JH, Davis SJ, Gold R, Nielsen FC, Siegel RM, Mann M, Bell JI, McVean G, Fugger L.

Nature. 2012 Aug 23;488(7412):508-511. doi: 10.1038/nature11307.

PubMed [citation]
PMID:
22801493
PMCID:
PMC4268493

Details of each submission

From OMIM, SCV000053359.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

Gregory et al. (2012) investigated the contribution of the single-nucleotide polymorphism (SNP) rs1800693 to susceptibility to multiple sclerosis associated with the TNFRSF1A region (MS5; 614810). The SNP rs1800693 is proximal to the TNFRSF1A exon 6/intron 6 boundary, and the G risk allele resulted in skipping of exon 6 in minigene splicing assays. In primary human immune cells, the presence of the risk allele correlated with increased expression of transcripts lacking exon 6. TNFR1 exon 6 skipping results in a frameshift and a premature stop codon, which translates into a protein comprising only the amino-terminal 183 amino acids of TNFR1 followed by a novel 45 amino acid sequence, as confirmed by tandem mass spectrometry. This mutant protein, delta-6-TNFR1, lacks the extracellular carboxy-terminal portion of the fourth cysteine-rich domain of the select protein, the transmembrane domain, and the intracellular region that is essential for appropriate subcellular localization. The mutant protein demonstrated a more diffuse intracellular distribution than the normal localization to the Golgi apparatus. Gregory et al. (2012) found no significant spontaneous NF-kappa-B (see 164011) signaling or TNFR1-mediated apoptosis upon delta-6-TNFR1 expression. However, the mutant protein could potentially retain some intracellular activity by accumulating in the endoplasmic reticulum and evoking a stress response. Gregory et al. (2012) concluded that the combined genetic and functional analyses strongly implicated rs1800693 as the causal SNP in the MS-associated TNFRSF1A region. Because the delta-6-TNFR1 protein is soluble and capable of TNF antagonism, Gregory et al. (2012) concluded that their evidence was consistent with the reported worsening of MS upon anti-TNF therapy.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024