rs5951308

chrX-101390479-T-AchrX-101390479-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000621635.4(BTK):c.71A>T(p.Glu24Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 8/10 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E24G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: BTK ENST00000621635.4 missense, splice_region
• Scores: Splicing: ADA: 0.00007013
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.113

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, BTK
• BP4: Computational evidence support a benign effect (MetaRNN=0.13571182).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTK	NM_001287344.2	c.71A>T	p.Glu24Val	missense_variant, splice_region_variant	1/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTK	ENST00000621635.4	c.71A>T	p.Glu24Val	missense_variant, splice_region_variant	1/19	1
BTK	ENST00000695633.1	n.282A>T		splice_region_variant, non_coding_transcript_exon_variant	1/3
BTK	ENST00000695634.1	n.282A>T		splice_region_variant, non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	4.4
Dann	Benign	0.54
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.14	T
Vest4		0.11
MVP		0.70
GERP RS		-0.88
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000070
dbscSNV1_RF	Benign	0.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs5951308; hg19: chrX-100645467;