X-101390479-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The ENST00000621635.4(BTK):c.71A>G(p.Glu24Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 512,948 control chromosomes in the GnomAD database, including 14,775 homozygotes. There are 42,588 hemizygotes in GnomAD. 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. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (7197 hom., 10801 hem., cov: 23)
  • Exomes 𝑓: 0.21 (7578 hom. 31787 hem.)
• Consequence: BTK ENST00000621635.4 missense, splice_region
• Scores: Splicing: ADA: 0.00007013
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, BTK
• BP4: Computational evidence support a benign effect (MetaRNN=9.4712937E-7).
• BP6: Variant X-101390479-T-C is Benign according to our data. Variant chrX-101390479-T-C is described in ClinVar as [Benign]. Clinvar id is 402436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTK	NM_001287344.2	c.71A>G	p.Glu24Gly	missense_variant, splice_region_variant	1/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTK	ENST00000621635.4	c.71A>G	p.Glu24Gly	missense_variant, splice_region_variant	1/19	1
BTK	ENST00000695633.1	n.282A>G		splice_region_variant, non_coding_transcript_exon_variant	1/3
BTK	ENST00000695634.1	n.282A>G		splice_region_variant, non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.331 AC: 36929 AN: 111516 Hom.: 7190 Cov.: 23 AF XY: 0.319 AC XY: 10755 AN XY: 33722

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.0990

Gnomad MID AF: 0.224

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.276

GnomAD3 exomes AF: 0.249 AC: 24340 AN: 97601 Hom.: 2827 AF XY: 0.246 AC XY: 8927 AN XY: 36345

Gnomad AFR exome AF: 0.769

Gnomad AMR exome AF: 0.294

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.131

Gnomad SAS exome AF: 0.402

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.212

GnomAD4 exome AF: 0.207 AC: 83233 AN: 401377 Hom.: 7578 Cov.: 0 AF XY: 0.214 AC XY: 31787 AN XY: 148815

Gnomad4 AFR exome AF: 0.752

Gnomad4 AMR exome AF: 0.292

Gnomad4 ASJ exome AF: 0.152

Gnomad4 EAS exome AF: 0.130

Gnomad4 SAS exome AF: 0.389

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.227

GnomAD4 genome AF: 0.331 AC: 36985 AN: 111571 Hom.: 7197 Cov.: 23 AF XY: 0.320 AC XY: 10801 AN XY: 33787

Gnomad4 AFR AF: 0.748

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.130

Gnomad4 SAS AF: 0.408

Gnomad4 FIN AF: 0.0990

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.279

Alfa AF: 0.255 Hom.: 3166

Bravo AF: 0.361

TwinsUK AF: 0.150 AC: 555

ALSPAC AF: 0.159 AC: 458

ExAC AF: 0.284 AC: 4231

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 38% of patients studied by a panel of primary immunodeficiencies. Number of patients: 36. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.89
Cadd	Benign	4.8
Dann	Benign	0.46
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	9.5e-7	T
Vest4		0.061
GERP RS		-0.88
gMVP		0.68

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; COSMIC: COSV58121598; COSMIC: COSV58121598;