rs864321665

Variant names:

• chrX-101362203-C-CT
• rs864321665
• NM_000061.3:c.557dupA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000061.3(BTK):​c.557dupA​(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 NM_000061.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.16
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Bruton-type agammaglobulinemia

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, ClinGen
• isolated growth hormone deficiency type III

  Inheritance: XL Classification: STRONG, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 11358.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.557dupA	p.Pro187AlafsTer7	frameshift_variant	Exon 7 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.659dupA	p.Pro221AlafsTer7	frameshift_variant	Exon 7 of 19		NP_001274273.1
BTK	NM_001287345.2	c.557dupA	p.Pro187AlafsTer7	frameshift_variant	Exon 8 of 17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.557dupA	p.Pro187AlafsTer7	frameshift_variant	Exon 7 of 19	1	NM_000061.3	ENSP00000308176.8

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

May 01, 2022

Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

X-linked agammaglobulinemia with growth hormone deficiency Pathogenic:1

Apr 17, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BTK are known to be pathogenic (PMID: 15661032, 16862044, 19419768). 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. This variant is not present in population databases (ExAC no frequency). 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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs864321665; hg19: chrX-100617191; COSMIC: COSV58118265;