rs1555977592
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000061.3(BTK):c.1581_1584del(p.Cys527TrpfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 22)
Consequence
BTK
NM_000061.3 frameshift
NM_000061.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.39
Genes affected
BTK (HGNC:1133): (Bruton tyrosine kinase) The protein encoded by this gene plays a crucial role in B-cell development. Mutations in this gene cause X-linked agammaglobulinemia type 1, which is an immunodeficiency characterized by the failure to produce mature B lymphocytes, and associated with a failure of Ig heavy chain rearrangement. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant X-101354676-CCAAA-C is Pathogenic according to our data. Variant chrX-101354676-CCAAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 492818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101354676-CCAAA-C is described in Lovd as [Pathogenic]. Variant chrX-101354676-CCAAA-C is described in Lovd as [Likely_pathogenic]. Variant chrX-101354676-CCAAA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BTK | NM_000061.3 | c.1581_1584del | p.Cys527TrpfsTer2 | frameshift_variant | 16/19 | ENST00000308731.8 | |
BTK | NM_001287344.2 | c.1683_1686del | p.Cys561TrpfsTer2 | frameshift_variant | 16/19 | ||
BTK | NM_001287345.2 | c.1053_1056del | p.Cys351TrpfsTer2 | frameshift_variant | 14/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BTK | ENST00000308731.8 | c.1581_1584del | p.Cys527TrpfsTer2 | frameshift_variant | 16/19 | 1 | NM_000061.3 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive agammaglobulinemia 1 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Oct 14, 2011 | - - |
X-linked agammaglobulinemia with growth hormone deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 492818). This premature translational stop signal has been observed in individual(s) with X-linked agammaglobulinemia (PMID: 20529312, 23424595, 27980540). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys527Trpfs*2) in the BTK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BTK are known to be pathogenic (PMID: 15661032, 16862044, 19419768). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 18, 2019 | 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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20529312, 23424595, 7849697, 27980540, 33225392, 32441320) - |
X-linked agammaglobulinemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1994 | - - |
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