rs193922128

Positions:

• chrX-101362605-GCTGT-G

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.472_475delACAG​(p.Thr158fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. 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: 23)
• Consequence: BTK NM_000061.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.55

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-101362605-GCTGT-G is Pathogenic according to our data. Variant chrX-101362605-GCTGT-G is described in ClinVar as [Pathogenic]. Clinvar id is 35761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101362605-GCTGT-G is described in Lovd as [Likely_pathogenic]. Variant chrX-101362605-GCTGT-G is described in Lovd as [Pathogenic]. Variant chrX-101362605-GCTGT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTK	NM_000061.3	c.472_475delACAG	p.Thr158fs	frameshift_variant	6/19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.574_577delACAG	p.Thr192fs	frameshift_variant	6/19		NP_001274273.1
BTK	NM_001287345.2	c.472_475delACAG	p.Thr158fs	frameshift_variant	7/17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.472_475delACAG	p.Thr158fs	frameshift_variant	6/19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 26, 2019

This sequence change creates a premature translational stop signal (p.Thr158Profs*17) 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 observed in individuals affected with X-linked agammaglobulinemia (PMID: 11742281, Invitae). This variant is also known as 604-607delACAG in the literature. ClinVar contains an entry for this variant (Variation ID: 35761). 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. -

X-linked agammaglobulinemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 17, 2019

Variant summary: BTK c.472_475delACAG (p.Thr158ProfsX17) 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 Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 183063 control chromosomes. c.472_475delACAG has been reported in the literature in an individual affected with X-linked Agammaglobulinemia confirmed to have very low levels of BTK protein expression (Kanegane_2001). At least one publication reports that this variant results in extremely low expression of BTK (Kanegane_2001). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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: rs193922128; hg19: chrX-100617593;