rs864321661

Positions:

• chrX-101375139-CTT-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000061.3(BTK):​c.141+3_141+4delAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: BTK NM_000061.3 splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.77

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-101375139-CTT-C is Pathogenic according to our data. Variant chrX-101375139-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 11353.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-101375139-CTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTK	NM_000061.3	c.141+3_141+4delAA		splice_region_variant, intron_variant		ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.243+3_243+4delAA		splice_region_variant, intron_variant			NP_001274273.1
BTK	NM_001287345.2	c.141+3_141+4delAA		splice_region_variant, intron_variant			NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.141+3_141+4delAA		splice_region_variant, intron_variant		1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 22

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

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked agammaglobulinemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: 24
DS_DL_spliceai		0.99		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs864321661; hg19: chrX-100630127;