chrX-101353203-G-A
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1
The NM_000061.3(BTK):c.1899C>T(p.Cys633=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,206,338 control chromosomes in the GnomAD database, including 32,609 homozygotes. There are 88,939 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.37 ( 8809 hom., 11848 hem., cov: 22)
Exomes 𝑓: 0.21 ( 23800 hom. 77091 hem. )
Consequence
BTK
NM_000061.3 synonymous
NM_000061.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 2.50
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 Benign. Variant got -16 ACMG points.
BP6
Variant X-101353203-G-A is Benign according to our data. Variant chrX-101353203-G-A is described in ClinVar as [Benign]. Clinvar id is 254784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101353203-G-A is described in Lovd as [Benign]. Variant chrX-101353203-G-A is described in Lovd as [Pathogenic].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BTK | NM_000061.3 | c.1899C>T | p.Cys633= | synonymous_variant | 18/19 | ENST00000308731.8 | |
BTK | NM_001287344.2 | c.2001C>T | p.Cys667= | synonymous_variant | 18/19 | ||
BTK | NM_001287345.2 | c.1371C>T | p.Cys457= | synonymous_variant | 16/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BTK | ENST00000308731.8 | c.1899C>T | p.Cys633= | synonymous_variant | 18/19 | 1 | NM_000061.3 | P3 |
Frequencies
GnomAD3 genomes AF: 0.373 AC: 41024AN: 110014Hom.: 8803 Cov.: 22 AF XY: 0.366 AC XY: 11797AN XY: 32274
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GnomAD3 exomes AF: 0.314 AC: 57197AN: 182369Hom.: 9111 AF XY: 0.288 AC XY: 19284AN XY: 66879
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GnomAD4 exome AF: 0.210 AC: 230566AN: 1096272Hom.: 23800 Cov.: 31 AF XY: 0.213 AC XY: 77091AN XY: 362110
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GnomAD4 genome AF: 0.373 AC: 41088AN: 110066Hom.: 8809 Cov.: 22 AF XY: 0.366 AC XY: 11848AN XY: 32336
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ClinVar
Significance: Benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 14, 2020 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 11, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan | Jan 24, 2024 | This variant is classified as Benign based on local population frequency. This variant was detected in 53% of patients studied by a panel of primary immunodeficiencies. Number of patients: 50. Only high quality variants are reported. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 28, 2016 | - - |
X-linked agammaglobulinemia with growth hormone deficiency Benign:3
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
X-linked agammaglobulinemia Benign:2
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 24
Find out detailed SpliceAI scores and Pangolin per-transcript scores at