rs886037654
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_013335.4(GMPPA):c.210del(p.Ala71ProfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
GMPPA
NM_013335.4 frameshift
NM_013335.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.89
Genes affected
GMPPA (HGNC:22923): (GDP-mannose pyrophosphorylase A) This gene is thought to encode a GDP-mannose pyrophosphorylase. This enzyme catalyzes the reaction which converts mannose-1-phosphate and GTP to GDP-mannose which is involved in the production of N-linked oligosaccharides. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 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 2-219501545-GA-G is Pathogenic according to our data. Variant chr2-219501545-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 88694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GMPPA | NM_013335.4 | c.210del | p.Ala71ProfsTer19 | frameshift_variant | 4/13 | ENST00000313597.10 | |
ASIC4-AS1 | XR_923921.2 | n.391+15150del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GMPPA | ENST00000313597.10 | c.210del | p.Ala71ProfsTer19 | frameshift_variant | 4/13 | 1 | NM_013335.4 | P1 | |
ASIC4-AS1 | ENST00000429882.1 | n.182+15150del | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460452Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 726656
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GnomAD4 genome ? Cov.: 32
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Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Global developmental delay;C4317146:Gastroesophageal reflux Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jan 22, 2020 | The c.210del, p.Ala71ProfsTer19 is a frameshift variant in GMPPA gene and has been reported in a patient with Alacrima, achalasia, and mental retardation syndrome [MIM#615510] [PMID: 24035193]. This variant is not reported in gnomAD database, indicating this is a rare allele. The detected variant causes a 1 bp deletion at amino acid 71, which is predicted to cause a frameshift and premature stop further downstream and in silico tool predicts the variant is expected to result in an absent protein product through nonsense-mediated mRNA decay [PMID: 24681721]. Based on the available evidence, the variant c.210del,p.Ala71ProfsTer19 in the GMPPA gene is classified as pathogenic. - |
Alacrima, achalasia, and intellectual disability syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 03, 2013 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24035193) - |
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