X-101390479-T-C

Position:

chrX-101390479-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001287344.2(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
NM_001287344.2 missense, splice_region

Scores

Splicing: ADA: 0.00007013

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.113

Variant links:

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 links:

BTK (HGNC:):

BTK links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BTK. . Gene score misZ 4.0394 (greater than the threshold 3.09). GenCC has associacion of gene with short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia, Bruton-type agammaglobulinemia, isolated growth hormone deficiency type III.

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	Protein	UniProt
BTK	NM_001287344.2 linkuse as main transcript	c.71A>G	p.Glu24Gly	missense_variant, splice_region_variant	1/19		NP_001274273.1	Q06187-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
BTK	ENST00000621635.4 linkuse as main transcript	c.71A>G	p.Glu24Gly	missense_variant, splice_region_variant	1/19	1	ENSP00000483570.1	Q06187-2
BTK	ENST00000695633.1 linkuse as main transcript	n.282A>G		splice_region_variant, non_coding_transcript_exon_variant	1/3
BTK	ENST00000695634.1 linkuse as main transcript	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.:

AF XY:

0.319

AC XY:

10755

AN XY:

33722

show subpopulations

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

show subpopulations

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.:

AF XY:

0.214

AC XY:

31787

AN XY:

148815

show subpopulations

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.:

AF XY:

0.320

AC XY:

10801

AN XY:

33787

show subpopulations

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.88

BayesDel_noAF

Benign

-0.89

CADD

Benign

4.8

DANN

Benign

0.46

FATHMM_MKL

Benign

0.0021

LIST_S2

Benign

0.18

MetaRNN

Benign

9.5e-7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over