14-105855621-CTT-C
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The ENST00000637539.2(IGHM):c.506_507del(p.Lys169ArgfsTer84) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000637 in 628,146 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000064 ( 0 hom. )
Consequence
IGHM
ENST00000637539.2 frameshift
ENST00000637539.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.21
Genes affected
IGHM (HGNC:5541): (immunoglobulin heavy constant mu) Immunoglobulins (Ig) are the antigen recognition molecules of B cells. An Ig molecule is made up of 2 identical heavy chains and 2 identical light chains (see MIM 147200) joined by disulfide bonds so that each heavy chain is linked to a light chain and the 2 heavy chains are linked together. Each Ig heavy chain has an N-terminal variable (V) region containing the antigen-binding site and a C-terminal constant (C) region, encoded by an individual C region gene, that determines the isotype of the antibody and provides effector or signaling functions. The heavy chain V region is encoded by 1 each of 3 types of genes: V genes (see MIM 147070), joining (J) genes (see MIM 147010), and diversity (D) genes (see MIM 146910). The C region genes are clustered downstream of the V region genes within the heavy chain locus on chromosome 14. The IGHM gene encodes the C region of the mu heavy chain, which defines the IgM isotype. Naive B cells express the transmembrane forms of IgM and IgD (see IGHD; MIM 1471770) on their surface. During an antibody response, activated B cells can switch to the expression of individual downstream heavy chain C region genes by a process of somatic recombination known as isotype switching. In addition, secreted Ig forms that act as antibodies can be produced by alternative RNA processing of the heavy chain C region sequences. Although the membrane forms of all Ig isotypes are monomeric, secreted IgM forms pentamers, and occasionally hexamers, in plasma (summary by Janeway et al., 2005).[supplied by OMIM, Aug 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 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 14-105855621-CTT-C is Pathogenic according to our data. Variant chr14-105855621-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 14812.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IGHM | ENST00000637539.2 | c.506_507del | p.Lys169ArgfsTer84 | frameshift_variant | 2/6 | A2 | |||
IGHM | ENST00000390559.6 | c.506_507del | p.Lys169ArgfsTer84 | frameshift_variant | 2/4 | P3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000163 AC: 4AN: 245848Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 133606
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GnomAD4 exome AF: 0.00000637 AC: 4AN: 628146Hom.: 0 AF XY: 0.00000292 AC XY: 1AN XY: 342206
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Autosomal recessive agammaglobulinemia 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2002 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at