rs1556143529
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000370629.7(CD40LG):c.559del(p.Ala187LeufsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 23)
Consequence
CD40LG
ENST00000370629.7 frameshift
ENST00000370629.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.906
Genes affected
CD40LG (HGNC:11935): (CD40 ligand) The protein encoded by this gene is expressed on the surface of T cells. It regulates B cell function by engaging CD40 on the B cell surface. A defect in this gene results in an inability to undergo immunoglobulin class switch and is associated with hyper-IgM syndrome. [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 does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 29 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-136659187-AG-A is Pathogenic according to our data. Variant chrX-136659187-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 521393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CD40LG | NM_000074.3 | c.559del | p.Ala187LeufsTer4 | frameshift_variant | 5/5 | ENST00000370629.7 | NP_000065.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CD40LG | ENST00000370629.7 | c.559del | p.Ala187LeufsTer4 | frameshift_variant | 5/5 | 1 | NM_000074.3 | ENSP00000359663 | P1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hyper-IgM syndrome type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 11, 2023 | This sequence change creates a premature translational stop signal (p.Ala187Leufs*4) in the CD40LG gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 75 amino acid(s) of the CD40LG protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of X-linked hyper-IgM syndrome (PMID: 15358621, 35753512). This variant is also known as 580DelG . ClinVar contains an entry for this variant (Variation ID: 521393). This variant disrupts a region of the CD40LG protein in which other variant(s) (p.Gly257Asp) have been determined to be pathogenic (PMID: 10366125; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 22, 2017 | - - |
Computational scores
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Splicing
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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