rs128621201

Positions:

• chrX-101356060-G-A
• chrX-101356060-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000061.3(BTK):​c.1558C>T​(p.Arg520*) variant causes a stop gained change involving the alteration of a non-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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: BTK NM_000061.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.70

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-101356060-G-A is Pathogenic according to our data. Variant chrX-101356060-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101356060-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTK	NM_000061.3	c.1558C>T	p.Arg520*	stop_gained	15/19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.1660C>T	p.Arg554*	stop_gained	15/19		NP_001274273.1
BTK	NM_001287345.2	c.1039-1366C>T		intron_variant			NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.1558C>T	p.Arg520*	stop_gained	15/19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked agammaglobulinemia Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed stop gained c.1558C>T (p.Arg520Ter) variant in BTK gene has been previously reported in multiple individuals affected with Agammaglobulinemia (Tóth et al., 2009; Doğruel et al., 2019; Zhu et al., 1994). The p.Arg520Ter variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). The nucleotide change c.1558C>T in BTK is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal (p.Arg520Ter) in the BTK gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in BTK gene have been previously reported to be pathogenic (Tóth et al., 2009). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with X-linked agammaglobulinemia 1 (MIM#300755) and isolated growth hormone deficiency type III with agammaglobulinemia (MIM#307200). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic in individuals with X-linked agammaglobulinemia (ClinVar, PMID: 30072168). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Autosomal recessive agammaglobulinemia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Feb 14, 2008

- -

X-linked agammaglobulinemia with growth hormone deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change creates a premature translational stop signal (p.Arg520*) in the BTK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BTK are known to be pathogenic (PMID: 15661032, 16862044, 19419768). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with X-linked agammaglobulinemia (PMID: 7849721, 7880320, 30072168). This variant is also known as 1690C>T. ClinVar contains an entry for this variant (Variation ID: 11377). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 28, 2024

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11742281, 15661032, 19039656, 9445504, 27512878, 15661031, 25777788, 7849697, 9545398, 16712653, 31967259, 7880320, 22927353, 21518255, 8834236, 30072168, 29424453, 14974089, 32914284, 33686510, 25525159, 34134972, 34992599, 33225392) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.89	D
Vest4		0.95
GERP RS		3.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs128621201; hg19: chrX-100611048; COSMIC: COSV105163970; COSMIC: COSV105163970;