rs1554594329
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005515.4(MNX1):c.53_54insC(p.Arg19ThrfsTer37) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,416,418 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
MNX1
NM_005515.4 frameshift
NM_005515.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.78
Genes affected
MNX1 (HGNC:4979): (motor neuron and pancreas homeobox 1) This gene encodes a nuclear protein, which contains a homeobox domain and is a transcription factor. Mutations in this gene result in Currarino syndrome, an autosomic dominant congenital malformation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 39 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 7-157010297-T-TG is Pathogenic according to our data. Variant chr7-157010297-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 435883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MNX1 | NM_005515.4 | c.53_54insC | p.Arg19ThrfsTer37 | frameshift_variant | 1/3 | ENST00000252971.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MNX1 | ENST00000252971.11 | c.53_54insC | p.Arg19ThrfsTer37 | frameshift_variant | 1/3 | 1 | NM_005515.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000141 AC: 2AN: 1416418Hom.: 0 Cov.: 33 AF XY: 0.00000142 AC XY: 1AN XY: 703824
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703824
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Currarino triad Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 31, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 14, 2023 | This sequence change creates a premature translational stop signal (p.Arg19Thrfs*37) in the MNX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MNX1 are known to be pathogenic (PMID: 10631160, 10749657, 16254195, 24095820). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Currarino syndrome (PMID: 24095820). This variant is also known as p.Pro18ProfsX37. ClinVar contains an entry for this variant (Variation ID: 435883). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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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