X-101353935-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_000061.3(BTK):​c.1685G>A​(p.Arg562Gln) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R562P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

BTK
NM_000061.3 missense

Scores

9
5
3

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.13
Variant links:
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 13 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, 3 uncertain in NM_000061.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-101353935-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in the BTK gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 90 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 4.0394 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.977
PP5
Variant X-101353935-C-T is Pathogenic according to our data. Variant chrX-101353935-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2431408.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BTKNM_000061.3 linkc.1685G>A p.Arg562Gln missense_variant Exon 17 of 19 ENST00000308731.8 NP_000052.1 Q06187-1Q5JY90
BTKNM_001287344.2 linkc.1787G>A p.Arg596Gln missense_variant Exon 17 of 19 NP_001274273.1 Q06187-2
BTKNM_001287345.2 linkc.1157G>A p.Arg386Gln missense_variant Exon 15 of 17 NP_001274274.1 Q06187Q5JY90

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BTKENST00000308731.8 linkc.1685G>A p.Arg562Gln missense_variant Exon 17 of 19 1 NM_000061.3 ENSP00000308176.8 Q06187-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

X-linked agammaglobulinemia Pathogenic:1
Mar 30, 2022
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PM2 moderated, PM5 moderated, PP2 supporting, PP3 supporting -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.69
D;.;.;D
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.98
D;D;D;D
M_CAP
Pathogenic
0.75
D
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Uncertain
0.59
D
MutationAssessor
Benign
1.9
.;.;.;L
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-2.2
.;N;.;N
REVEL
Pathogenic
0.77
Sift
Uncertain
0.0090
.;D;.;D
Sift4G
Uncertain
0.0050
D;D;D;D
Polyphen
1.0
.;D;.;D
Vest4
0.85
MutPred
0.88
Gain of ubiquitination at K558 (P = 0.0641);.;.;Gain of ubiquitination at K558 (P = 0.0641);
MVP
0.99
MPC
2.6
ClinPred
0.96
D
GERP RS
5.5
Varity_R
0.97
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-100608923; COSMIC: COSV58120218; COSMIC: COSV58120218; API