Genetic Variant BTK:c.*342_*343dupTG (chrX-101349541-C-CCA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000061.3(BTK):c.*342_*343dupTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000354 in 226,269 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.000061 ( 0 hom. 0 hem. )

Consequence

BTK
NM_000061.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.224

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3 link	c.342_343dupTG	3_prime_UTR_variant	Exon 19 of 19	ENST00000308731.8	NP_000052.1	Q06187-1Q5JY90
BTK	NM_001287344.2 link	c.342_343dupTG	3_prime_UTR_variant	Exon 19 of 19		NP_001274273.1	Q06187-2
BTK	NM_001287345.2 link	c.342_343dupTG	3_prime_UTR_variant	Exon 17 of 17		NP_001274274.1	Q06187Q5JY90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8 link	c.342_343dupTG		3_prime_UTR_variant	Exon 19 of 19	1	NM_000061.3	ENSP00000308176.8		Q06187-1

Frequencies

GnomAD3 genomes

AF:

0.00000904

AC:

AN:

110612

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000605

AC:

AN:

115657

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

28667

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000210

AC:

AN:

4755

American (AMR)

AF:

0.00

AC:

AN:

5126

Ashkenazi Jewish (ASJ)

AF:

0.000208

AC:

AN:

4800

East Asian (EAS)

AF:

0.00

AC:

AN:

11731

South Asian (SAS)

AF:

0.000280

AC:

AN:

3577

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

535

European-Non Finnish (NFE)

AF:

0.0000547

AC:

AN:

73159

Other (OTH)

AF:

0.00

AC:

AN:

8392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000904

AC:

AN:

110612

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32840

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30350

American (AMR)

AF:

0.00

AC:

AN:

10322

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3557

South Asian (SAS)

AF:

0.00

AC:

AN:

2648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5818

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52874

Other (OTH)

AF:

0.00

AC:

AN:

1492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.22

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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X-101349541-CCA-CCACA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over