rs1135363

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000061.3(BTK):c.1899C>T(p.Cys633Cys) 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:11

Conservation

PhyloP100: 2.50

Publications

18 publications found

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 Gene-Disease associations (from GenCC):

Bruton-type agammaglobulinemia
Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, ClinGen
isolated growth hormone deficiency type III
Inheritance: XL Classification: STRONG, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

BTK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 254784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3 link	c.1899C>T	p.Cys633Cys	synonymous_variant	Exon 18 of 19	ENST00000308731.8	NP_000052.1	Q06187-1Q5JY90
BTK	NM_001287344.2 link	c.2001C>T	p.Cys667Cys	synonymous_variant	Exon 18 of 19		NP_001274273.1	Q06187-2
BTK	NM_001287345.2 link	c.1371C>T	p.Cys457Cys	synonymous_variant	Exon 16 of 17		NP_001274274.1	Q06187Q5JY90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8 link	c.1899C>T	p.Cys633Cys	synonymous_variant	Exon 18 of 19	1	NM_000061.3	ENSP00000308176.8		Q06187-1

Frequencies

GnomAD3 genomes

AF:

0.373

AC:

41024

AN:

110014

Hom.:

8803

Cov.:

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

GnomAD2 exomes

AF:

0.314

AC:

57197

AN:

182369

AF XY:

0.288

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 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

African (AFR)

AF:

0.828

AC:

21836

AN:

26359

American (AMR)

AF:

0.501

AC:

17617

AN:

35144

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

3044

AN:

19364

East Asian (EAS)

AF:

0.469

AC:

14148

AN:

30189

South Asian (SAS)

AF:

0.435

AC:

23440

AN:

53918

European-Finnish (FIN)

AF:

0.158

AC:

6403

AN:

40518

Middle Eastern (MID)

AF:

0.192

AC:

791

AN:

4110

European-Non Finnish (NFE)

AF:

0.157

AC:

131846

AN:

840647

Other (OTH)

AF:

0.249

AC:

11441

AN:

46023

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

5261

10522

15783

21044

26305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5472

10944

16416

21888

27360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.373

AC:

41088

AN:

110066

Hom.:

8809

Cov.:

AF XY:

0.366

AC XY:

11848

AN XY:

32336

show subpopulations

African (AFR)

AF:

0.808

AC:

24344

AN:

30128

American (AMR)

AF:

0.374

AC:

3834

AN:

10248

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

414

AN:

2631

East Asian (EAS)

AF:

0.440

AC:

1537

AN:

3496

South Asian (SAS)

AF:

0.448

AC:

1160

AN:

2592

European-Finnish (FIN)

AF:

0.157

AC:

905

AN:

5770

Middle Eastern (MID)

AF:

0.207

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.157

AC:

8301

AN:

52818

Other (OTH)

AF:

0.323

AC:

481

AN:

1487

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

593

1185

1778

2370

2963

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

364

728

1092

1456

1820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.221

Hom.:

8305

Bravo

AF:

0.415

EpiCase

AF:

0.161

EpiControl

AF:

0.151

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jan 28, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 11, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dec 14, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

X-linked agammaglobulinemia with growth hormone deficiency

Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked agammaglobulinemia

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.64

PhyloP100

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over