rs104894770

Positions:

• chrX-101353935-C-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000061.3(BTK):​c.1685G>C​(p.Arg562Pro) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R562Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.13

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]

ACMG classification

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, 2 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-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2431408.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, BTK
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant X-101353935-C-G is Pathogenic according to our data. Variant chrX-101353935-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 11394.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-101353935-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTK	NM_000061.3	c.1685G>C	p.Arg562Pro	missense_variant	17/19	ENST00000308731.8
BTK	NM_001287344.2	c.1787G>C	p.Arg596Pro	missense_variant	17/19
BTK	NM_001287345.2	c.1157G>C	p.Arg386Pro	missense_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTK	ENST00000308731.8	c.1685G>C	p.Arg562Pro	missense_variant	17/19	1	NM_000061.3	P3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 20, 2015

The R562P missense variant in the BTK gene has been reported previously in association withX-linked agammaglobulinemia (Vihinen et al., 1994; Curtis et al., 2000). This pathogenic variant occurs in the protein kinasedomain of the BTK protein near other residues with reported pathogenic variants (Vihinen et al.,1994). R562P impairs the kinase activity of the resulting protein despite a lack of effect on proteinlevels (Maniar et al., 1995). Additionally, the R562P variant was not observed in approximately6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. Therefore, we interpret R562P as a pathogenic variant. -

X-linked agammaglobulinemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 31, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;.;D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.87	D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.98
MutPred		0.88		Gain of catalytic residue at W563 (P = 0.0184);.;.;Gain of catalytic residue at W563 (P = 0.0184);
MVP		0.99
MPC		3.1
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.99
gMVP		1.0

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: rs104894770; hg19: chrX-100608923;