rs128621192

Positions:

• chrX-101360589-C-T

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.755G>A​(p.Trp252Ter) variant causes a stop gained 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: BTK NM_000061.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.12

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 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-101360589-C-T is Pathogenic according to our data. Variant chrX-101360589-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101360589-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.755G>A	p.Trp252Ter	stop_gained	8/19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.857G>A	p.Trp286Ter	stop_gained	8/19		NP_001274273.1
BTK	NM_001287345.2	c.755G>A	p.Trp252Ter	stop_gained	9/17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.755G>A	p.Trp252Ter	stop_gained	8/19	1	NM_000061.3	ENSP00000308176	P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked agammaglobulinemia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 06, 2023	Variant summary: BTK c.755G>A (p.Trp252X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 183226 control chromosomes (gnomAD). The variant, c.755G>A, has been reported in the literature in individuals affected with X-linked Agammaglobulinemia (examples: Conley_1998, Chen_2016). In addition, another variant, c.756G>A, resulting in the same nonsense mutation (p.Trp252X) has been reported in affected individuals (Holinski-Feder_1998, Kanegane_2001). The following publications have been ascertained in the context of this evaluation (PMID: 27512878, 9545398, 7849697, 9445504, 11742281). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

X-linked agammaglobulinemia with growth hormone deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 18, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 11362). This premature translational stop signal has been observed in individual(s) with clinical features of BTK-related conditions (PMID: 7849697, 9445504). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp252*) 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A
Vest4		0.96
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs128621192; hg19: chrX-100615577;