rs1135363

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000061.3(BTK):c.1899C>T(p.Cys633=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,206,338 control chromosomes in the GnomAD database, including 32,609 homozygotes. There are 88,939 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 8809 hom., 11848 hem., cov: 22)

Exomes 𝑓: 0.21 ( 23800 hom. 77091 hem. )

Consequence

BTK
NM_000061.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.50

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant X-101353203-G-A is Benign according to our data. Variant chrX-101353203-G-A is described in ClinVar as [Benign]. Clinvar id is 254784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101353203-G-A is described in Lovd as [Benign]. Variant chrX-101353203-G-A is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
BTK	NM_000061.3 linkuse as main transcript	c.1899C>T	p.Cys633=	synonymous_variant	18/19	ENST00000308731.8
BTK	NM_001287344.2 linkuse as main transcript	c.2001C>T	p.Cys667=	synonymous_variant	18/19
BTK	NM_001287345.2 linkuse as main transcript	c.1371C>T	p.Cys457=	synonymous_variant	16/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTK	ENST00000308731.8 linkuse as main transcript	c.1899C>T	p.Cys633=	synonymous_variant	18/19	1	NM_000061.3	P3	Q06187-1

Frequencies

GnomAD3 genomes

AF:

0.373

AC:

41024

AN:

110014

Hom.:

8803

Cov.:

AF XY:

0.366

AC XY:

11797

AN XY:

32274

show subpopulations

Gnomad AFR

AF:

0.808

Gnomad AMI

AF:

0.0987

Gnomad AMR

AF:

0.374

Gnomad ASJ

AF:

0.157

Gnomad EAS

AF:

0.440

Gnomad SAS

AF:

0.448

Gnomad FIN

AF:

0.157

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.319

GnomAD3 exomes

AF:

0.314

AC:

57197

AN:

182369

Hom.:

9111

AF XY:

0.288

AC XY:

19284

AN XY:

66879

show subpopulations

Gnomad AFR exome

AF:

0.821

Gnomad AMR exome

AF:

0.518

Gnomad ASJ exome

AF:

0.151

Gnomad EAS exome

AF:

0.446

Gnomad SAS exome

AF:

0.448

Gnomad FIN exome

AF:

0.160

Gnomad NFE exome

AF:

0.160

Gnomad OTH exome

AF:

0.243

GnomAD4 exome

AF:

0.210

AC:

230566

AN:

1096272

Hom.:

23800

Cov.:

AF XY:

0.213

AC XY:

77091

AN XY:

362110

show subpopulations

Gnomad4 AFR exome

AF:

0.828

Gnomad4 AMR exome

AF:

0.501

Gnomad4 ASJ exome

AF:

0.157

Gnomad4 EAS exome

AF:

0.469

Gnomad4 SAS exome

AF:

0.435

Gnomad4 FIN exome

AF:

0.158

Gnomad4 NFE exome

AF:

0.157

Gnomad4 OTH exome

AF:

0.249

GnomAD4 genome

AF:

0.373

AC:

41088

AN:

110066

Hom.:

8809

Cov.:

AF XY:

0.366

AC XY:

11848

AN XY:

32336

show subpopulations

Gnomad4 AFR

AF:

0.808

Gnomad4 AMR

AF:

0.374

Gnomad4 ASJ

AF:

0.157

Gnomad4 EAS

AF:

0.440

Gnomad4 SAS

AF:

0.448

Gnomad4 FIN

AF:

0.157

Gnomad4 NFE

AF:

0.157

Gnomad4 OTH

AF:

0.323

Alfa

AF:

0.212

Hom.:

6496

Bravo

AF:

0.415

EpiCase

AF:

0.161

EpiControl

AF:

0.151

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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 53% of patients studied by a panel of primary immunodeficiencies. Number of patients: 50. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 14, 2020	proposed classification - variant undergoing re-assessment, contact laboratory -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

X-linked agammaglobulinemia with growth hormone deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

X-linked agammaglobulinemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

Cadd

Benign

Dann

Benign

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.22

Position offset: 24

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