rs128620183

Positions:

• chrX-101354687-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000061.3(BTK):​c.1574G>A​(p.Arg525Gln) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R525P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.82

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]

BTK (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a domain Protein kinase (size 253) in uniprot entity BTK_HUMAN there are 43 pathogenic changes around while only 1 benign (98%) 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 chrnull-null-null-null is described in UniProt as null.
• 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, 0.996
• PP5: Variant X-101354687-C-T is Pathogenic according to our data. Variant chrX-101354687-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101354687-C-T is described in Lovd as [Pathogenic]. Variant chrX-101354687-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTK	NM_000061.3	c.1574G>A	p.Arg525Gln	missense_variant	16/19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.1676G>A	p.Arg559Gln	missense_variant	16/19		NP_001274273.1
BTK	NM_001287345.2	c.1046G>A	p.Arg349Gln	missense_variant	14/17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.1574G>A	p.Arg525Gln	missense_variant	16/19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked agammaglobulinemia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 13, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

Autosomal recessive agammaglobulinemia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Feb 17, 2017

- -

X-linked agammaglobulinemia with growth hormone deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 525 of the BTK protein (p.Arg525Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with X-linked agammaglobulinemia (PMID: 9445504, 11742281, 19039656). In at least one individual the variant was observed to be de novo. This variant is also known as c.1706G>A. ClinVar contains an entry for this variant (Variation ID: 11342). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BTK protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;.;.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	1.0	D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.7	.;.;.;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.6	.;D;.;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0070	.;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0, 1.0	.;D;.;D
Vest4		0.99
MutPred		0.94		Loss of helix (P = 0.3949);.;.;Loss of helix (P = 0.3949);
MVP		1.0
MPC		1.6
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.97

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

LitVar

Other links and lift over

dbSNP: rs128620183; hg19: chrX-100609675; COSMIC: COSV58123749; COSMIC: COSV58123749;