rs864321665

Positions:

• chrX-101362203-C-CT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000308731.8(BTK):​c.557_558insA​(p.Pro187AlafsTer7) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: BTK ENST00000308731.8 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.16

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 12 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-101362203-C-CT is Pathogenic according to our data. Variant chrX-101362203-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 11358.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTK	NM_000061.3	c.557_558insA	p.Pro187AlafsTer7	frameshift_variant	7/19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.659_660insA	p.Pro221AlafsTer7	frameshift_variant	7/19		NP_001274273.1
BTK	NM_001287345.2	c.557_558insA	p.Pro187AlafsTer7	frameshift_variant	8/17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.557_558insA	p.Pro187AlafsTer7	frameshift_variant	7/19	1	NM_000061.3	ENSP00000308176	P3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked agammaglobulinemia Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	May 01, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1994	- -

X-linked agammaglobulinemia with growth hormone deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 17, 2018

This sequence change creates a premature translational stop signal (p.Pro187Alafs*7) in the BTK gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with X-linked agammaglobulinemia (PMID: 9143921, 7849697). ClinVar contains an entry for this variant (Variation ID: 11358). This variant is also known as insA [684-689] and A insertion at codon 186 in the literature. Loss-of-function variants in BTK are known to be pathogenic (PMID: 15661032, 16862044, 19419768). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs864321665; hg19: chrX-100617191;