rs128621196
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5
The NM_000061.3(BTK):c.1001A>C(p.Tyr334Ser) 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 Pathogenic (no stars).
Frequency
Genomes: not found (cov: 23)
Consequence
BTK
NM_000061.3 missense
NM_000061.3 missense
Scores
9
3
1
Clinical Significance
Conservation
PhyloP100: 7.80
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000061.3
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, BTK
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
?
Variant X-101358411-T-G is Pathogenic according to our data. Variant chrX-101358411-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 11368.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-101358411-T-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BTK | NM_000061.3 | c.1001A>C | p.Tyr334Ser | missense_variant | 12/19 | ENST00000308731.8 | |
BTK | NM_001287344.2 | c.1103A>C | p.Tyr368Ser | missense_variant | 12/19 | ||
BTK | NM_001287345.2 | c.1001A>C | p.Tyr334Ser | missense_variant | 13/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BTK | ENST00000308731.8 | c.1001A>C | p.Tyr334Ser | missense_variant | 12/19 | 1 | NM_000061.3 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
X-linked agammaglobulinemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1994 | - - |
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
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A
PrimateAI
Pathogenic
D
Sift4G
Uncertain
D;D;D;D
Polyphen
0.99, 1.0
.;D;.;D
Vest4
MutPred
Gain of disorder (P = 0.0326);Gain of disorder (P = 0.0326);.;Gain of disorder (P = 0.0326);
MVP
MPC
3.1
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at