rs1553578407
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_016653.3(MAP3K20):c.515G>A(p.Trp172Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
MAP3K20
NM_016653.3 stop_gained
NM_016653.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 9.91
Genes affected
MAP3K20 (HGNC:17797): (mitogen-activated protein kinase kinase kinase 20) This gene is a member of the MAPKKK family of signal transduction molecules and encodes a protein with an N-terminal kinase catalytic domain, followed by a leucine zipper motif and a sterile-alpha motif (SAM). This magnesium-binding protein forms homodimers and is located in the cytoplasm. The protein mediates gamma radiation signaling leading to cell cycle arrest and activity of this protein plays a role in cell cycle checkpoint regulation in cells. The protein also has pro-apoptotic activity. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-173191110-G-A is Pathogenic according to our data. Variant chr2-173191110-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 446159.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAP3K20 | NM_016653.3 | c.515G>A | p.Trp172Ter | stop_gained | 7/20 | ENST00000375213.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAP3K20 | ENST00000375213.8 | c.515G>A | p.Trp172Ter | stop_gained | 7/20 | 1 | NM_016653.3 | P1 | |
MAP3K20-AS1 | ENST00000422703.5 | n.338+1831C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461754Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727174
GnomAD4 exome
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2
AN:
1461754
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32
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0
AN XY:
727174
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Myopathy, centronuclear, 6, with fiber-type disproportion Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 07, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 19, 2022 | ClinVar contains an entry for this variant (Variation ID: 446159). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with congenital myopathy (PMID: 27816943). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp172*) in the MAP3K20 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAP3K20 are known to be pathogenic (PMID: 27816943). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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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