rs193922125
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate
The ENST00000308731.8(BTK):c.1511A>T(p.Asp504Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 22)
Consequence
BTK
ENST00000308731.8 missense
ENST00000308731.8 missense
Scores
15
1
1
Clinical Significance
Conservation
PhyloP100: 8.02
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 11 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000308731.8
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BTK. . Gene score misZ 4.0394 (greater than the threshold 3.09). GenCC has associacion of gene with short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia, Bruton-type agammaglobulinemia, isolated growth hormone deficiency type III.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant X-101356107-T-A is Pathogenic according to our data. Variant chrX-101356107-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35758.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-101356107-T-A is described in Lovd as [Pathogenic]. Variant chrX-101356107-T-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BTK | NM_000061.3 | c.1511A>T | p.Asp504Val | missense_variant | 15/19 | ENST00000308731.8 | NP_000052.1 | |
BTK | NM_001287344.2 | c.1613A>T | p.Asp538Val | missense_variant | 15/19 | NP_001274273.1 | ||
BTK | NM_001287345.2 | c.1039-1413A>T | intron_variant | NP_001274274.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BTK | ENST00000308731.8 | c.1511A>T | p.Asp504Val | missense_variant | 15/19 | 1 | NM_000061.3 | ENSP00000308176 | P3 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 genomes
Cov.:
22
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 22
GnomAD4 genome
Cov.:
22
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
X-linked agammaglobulinemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;D
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;.;D
REVEL
Pathogenic
Sift
Pathogenic
.;.;D
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;.;D
Vest4
MutPred
Gain of methylation at K503 (P = 0.0458);.;Gain of methylation at K503 (P = 0.0458);
MVP
MPC
3.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at