rs150917517

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP7BS2

The NM_000061.3(BTK):c.390C>T(p.Asn130Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000025 in 1,202,198 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000018 ( 0 hom. 6 hem. )

Consequence

BTK
NM_000061.3 splice_region, synonymous

Scores

Splicing: ADA: 0.001158

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.984

Publications

0 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP7

Synonymous conserved (PhyloP=-0.984 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
BTK	NM_000061.3 link	c.390C>T	p.Asn130Asn	splice_region_variant, synonymous_variant	Exon 5 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2 link	c.492C>T	p.Asn164Asn	splice_region_variant, synonymous_variant	Exon 5 of 19		NP_001274273.1
BTK	NM_001287345.2 link	c.390C>T	p.Asn130Asn	splice_region_variant, synonymous_variant	Exon 6 of 17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8 link	c.390C>T	p.Asn130Asn	splice_region_variant, synonymous_variant	Exon 5 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes

AF:

0.0000916

AC:

AN:

109143

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000301

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000220

AC:

AN:

182216

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000307

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000183

AC:

AN:

1093055

Hom.:

Cov.:

AF XY:

0.0000167

AC XY:

AN XY:

358853

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26302

American (AMR)

AF:

0.00

AC:

AN:

35172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19323

East Asian (EAS)

AF:

0.00

AC:

AN:

30134

South Asian (SAS)

AF:

0.00

AC:

AN:

53871

European-Finnish (FIN)

AF:

0.0000248

AC:

AN:

40379

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4122

European-Non Finnish (NFE)

AF:

0.0000191

AC:

AN:

837830

Other (OTH)

AF:

0.00

AC:

AN:

45922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000916

AC:

AN:

109143

Hom.:

Cov.:

AF XY:

0.0000628

AC XY:

AN XY:

31845

show subpopulations

African (AFR)

AF:

0.000301

AC:

AN:

29905

American (AMR)

AF:

0.00

AC:

AN:

10010

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2633

East Asian (EAS)

AF:

0.00

AC:

AN:

3532

South Asian (SAS)

AF:

0.00

AC:

AN:

2569

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5567

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

52563

Other (OTH)

AF:

0.00

AC:

AN:

1459

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.0000687

Hom.:

Bravo

AF:

0.0000907

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency

Uncertain:1

Apr 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 130 of the BTK mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BTK protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs150917517, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BTK-related conditions. ClinVar contains an entry for this variant (Variation ID: 573075). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

4.7

(source)

DANN

Benign

0.76

PhyloP100

-0.98

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0012

dbscSNV1_RF

Benign

0.044

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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