rs549858466
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_003954.5(MAP3K14):c.2433+3G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,573,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
MAP3K14
NM_003954.5 splice_donor_region, intron
NM_003954.5 splice_donor_region, intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.138
Genes affected
MAP3K14 (HGNC:6853): (mitogen-activated protein kinase kinase kinase 14) This gene encodes mitogen-activated protein kinase kinase kinase 14, which is a serine/threonine protein-kinase. This kinase binds to TRAF2 and stimulates NF-kappaB activity. It shares sequence similarity with several other MAPKK kinases. It participates in an NF-kappaB-inducing signalling cascade common to receptors of the tumour-necrosis/nerve-growth factor (TNF/NGF) family and to the interleukin-1 type-I receptor. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.53).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAP3K14 | NM_003954.5 | c.2433+3G>A | splice_donor_region_variant, intron_variant | ENST00000344686.8 | |||
MAP3K14-AS1 | NR_110325.1 | n.260-24C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAP3K14 | ENST00000344686.8 | c.2433+3G>A | splice_donor_region_variant, intron_variant | 1 | NM_003954.5 | P1 | |||
MAP3K14-AS1 | ENST00000657572.1 | n.170-24C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000370 AC: 7AN: 189092Hom.: 0 AF XY: 0.0000588 AC XY: 6AN XY: 101976
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GnomAD4 exome AF: 0.0000106 AC: 15AN: 1421554Hom.: 0 Cov.: 31 AF XY: 0.0000114 AC XY: 8AN XY: 703742
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74470
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
NIK deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 13, 2018 | This sequence change falls in intron 13 of the MAP3K14 gene. It does not directly change the encoded amino acid sequence of the MAP3K14 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs549858466, ExAC 0.2%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with MAP3K14-related disease. - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at