chr9-137087074-C-CG
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_016219.5(MAN1B1):c.79dup(p.Ala27GlyfsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,450,440 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
MAN1B1
NM_016219.5 frameshift
NM_016219.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.413
Genes affected
MAN1B1 (HGNC:6823): (mannosidase alpha class 1B member 1) This gene encodes an enzyme belonging to the glycosyl hydrolase 47 family. This enzyme functions in N-glycan biosynthesis, and is a class I alpha-1,2-mannosidase that specifically converts Man9GlcNAc to Man8GlcNAc isomer B. It is required for N-glycan trimming to Man5-6GlcNAc2 in the endoplasmic-reticulum-associated degradation pathway. Mutations in this gene cause autosomal-recessive intellectual disability. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 11. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 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 30 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-137087074-C-CG is Pathogenic according to our data. Variant chr9-137087074-C-CG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 632038.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAN1B1 | NM_016219.5 | c.79dup | p.Ala27GlyfsTer35 | frameshift_variant | 1/13 | ENST00000371589.9 | |
MAN1B1 | XM_006716945.5 | c.79dup | p.Ala27GlyfsTer35 | frameshift_variant | 1/12 | ||
MAN1B1 | NR_045720.2 | n.94dup | non_coding_transcript_exon_variant | 1/13 | |||
MAN1B1 | NR_045721.2 | n.94dup | non_coding_transcript_exon_variant | 1/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAN1B1 | ENST00000371589.9 | c.79dup | p.Ala27GlyfsTer35 | frameshift_variant | 1/13 | 1 | NM_016219.5 | P2 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
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34
GnomAD4 exome AF: 0.00000207 AC: 3AN: 1450440Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2AN XY: 720578
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GnomAD4 genome Cov.: 34
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 13, 2018 | The c.79dupG pathogenic mutation, located in coding exon 1 of the MAN1B1 gene, results from a duplication of G at nucleotide position 79, causing a translational frameshift with a predicted alternate stop codon (p.A27Gfs*35). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Rafiq syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The MAN1B1 c.79dupG (p.Ala27GlyfsTer35) variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive intellectual disability. - |
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