dbSNP rs183674618: BTK:c.*334T>G (chrX-101349551-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000061.3(BTK):c.*334T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 229,791 control chromosomes in the GnomAD database, including 113 homozygotes. There are 668 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 100 hom., 605 hem., cov: 22)

Exomes 𝑓: 0.0039 ( 13 hom. 63 hem. )

Consequence

BTK
NM_000061.3 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.347

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant X-101349551-A-C is Benign according to our data. Variant chrX-101349551-A-C is described in ClinVar as [Benign]. Clinvar id is 367692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0842 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3 link	c.*334T>G	3_prime_UTR_variant	Exon 19 of 19	ENST00000308731.8	NP_000052.1	Q06187-1Q5JY90
BTK	NM_001287344.2 link	c.*334T>G	3_prime_UTR_variant	Exon 19 of 19		NP_001274273.1	Q06187-2
BTK	NM_001287345.2 link	c.*334T>G	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 link	c.*334T>G		3_prime_UTR_variant	Exon 19 of 19	1	NM_000061.3	ENSP00000308176.8		Q06187-1

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

2717

AN:

108243

Hom.:

Cov.:

AF XY:

0.0193

AC XY:

602

AN XY:

31173

show subpopulations

Gnomad AFR

AF:

0.0869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00117

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0338

Gnomad NFE

AF:

0.000346

Gnomad OTH

AF:

0.0111

GnomAD4 exome

AF:

0.00385

AC:

468

AN:

121500

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

AN XY:

29584

show subpopulations

Gnomad4 AFR exome

AF:

0.0677

Gnomad4 AMR exome

AF:

0.00664

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000220

Gnomad4 OTH exome

AF:

0.00882

GnomAD4 genome

AF:

0.0252

AC:

2724

AN:

108291

Hom.:

100

Cov.:

AF XY:

0.0194

AC XY:

605

AN XY:

31231

show subpopulations

Gnomad4 AFR

AF:

0.0870

Gnomad4 AMR

AF:

0.0106

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00117

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000346

Gnomad4 OTH

AF:

0.0110

Alfa

AF:

0.0227

Hom.:

Bravo

AF:

0.0316

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency

Benign:1

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

X-linked agammaglobulinemia

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

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

-0.85

CADD

Benign

3.4

DANN

Benign

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

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

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