rs104894770

Variant names:

• chrX-101353935-C-G
• rs104894770
• NM_000061.3:c.1685G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-101353935-C-G
• chrX-101353935-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.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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R562W) has been classified as 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:3
• 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 19 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-101353936-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11383.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, 0.989
• PP5: Variant X-101353935-C-G is Pathogenic according to our data. 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. Variant chrX-101353935-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.1685G>C	p.Arg562Pro	missense_variant	Exon 17 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.1787G>C	p.Arg596Pro	missense_variant	Exon 17 of 19		NP_001274273.1
BTK	NM_001287345.2	c.1157G>C	p.Arg386Pro	missense_variant	Exon 15 of 17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.1685G>C	p.Arg562Pro	missense_variant	Exon 17 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency Pathogenic:1

Apr 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 562 of the BTK protein (p.Arg562Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with agammaglobulinemia (PMID: 7809124, 10678660). ClinVar contains an entry for this variant (Variation ID: 11394). 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%. This variant disrupts the p.Arg562 amino acid residue in BTK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7880320, 11742281, 16951917, 17765309, 19904586). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Aug 20, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 31, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
MutationAssessor	Benign	2.0	.;.;.;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.5	.;D;.;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0030	.;D;.;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;