rs138411530

Positions:

• chrX-101375133-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000061.3(BTK):​c.141+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00773 in 1,209,389 control chromosomes in the GnomAD database, including 29 homozygotes. There are 2,872 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0061 (1 hom., 175 hem., cov: 23)
  • Exomes 𝑓: 0.0079 (28 hom. 2697 hem.)
• Consequence: BTK NM_000061.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -0.328

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-101375133-G-A is Benign according to our data. Variant chrX-101375133-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235712.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=6, Uncertain_significance=1}. Variant chrX-101375133-G-A is described in Lovd as [Likely_benign]. Variant chrX-101375133-G-A is described in Lovd as [Pathogenic]. Variant chrX-101375133-G-A is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00605 (677/111866) while in subpopulation AMR AF= 0.0128 (134/10480). AF 95% confidence interval is 0.011. There are 1 homozygotes in gnomad4. There are 175 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 175 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTK	NM_000061.3	c.141+11C>T		intron_variant		ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.243+11C>T		intron_variant			NP_001274273.1
BTK	NM_001287345.2	c.141+11C>T		intron_variant			NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.141+11C>T		intron_variant		1	NM_000061.3	ENSP00000308176	P3

Frequencies

GnomAD3 genomes AF: 0.00605 AC: 677 AN: 111813 Hom.: 1 Cov.: 23 AF XY: 0.00515 AC XY: 175 AN XY: 33993

Gnomad AFR AF: 0.000975

Gnomad AMI AF: 0.00146

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00532

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00885

Gnomad OTH AF: 0.00597

GnomAD3 exomes AF: 0.00482 AC: 882 AN: 183166 Hom.: 1 AF XY: 0.00477 AC XY: 323 AN XY: 67704

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00576

Gnomad NFE exome AF: 0.00813

Gnomad OTH exome AF: 0.00553

GnomAD4 exome AF: 0.00790 AC: 8667 AN: 1097523 Hom.: 28 Cov.: 30 AF XY: 0.00743 AC XY: 2697 AN XY: 362901

Gnomad4 AFR exome AF: 0.000947

Gnomad4 AMR exome AF: 0.00347

Gnomad4 ASJ exome AF: 0.000155

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000739

Gnomad4 FIN exome AF: 0.00652

Gnomad4 NFE exome AF: 0.00946

Gnomad4 OTH exome AF: 0.00614

GnomAD4 genome AF: 0.00605 AC: 677 AN: 111866 Hom.: 1 Cov.: 23 AF XY: 0.00514 AC XY: 175 AN XY: 34056

Gnomad4 AFR AF: 0.000973

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00532

Gnomad4 NFE AF: 0.00885

Gnomad4 OTH AF: 0.00590

Alfa AF: 0.00786 Hom.: 187

Bravo AF: 0.00666

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	BTK: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 03, 2017	Variant summary: The BTK c.141+11C>T variant involves the alteration of a non-conserved intronic nucleotide. Mutation tested predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. These predictions have yet to be confirmed by functional studies. This variant was found in the large control population database ExAC (410/87888 control chromosomes including 160 hemizygotes) at a frequency of 0.004665, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic BTK variant (0.0023049), suggesting this variant is likely a benign polymorphism. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely benign or benign. Published studies als support for benign outcome -- this variant was found not to cosegregate with XLA in a family (Conley_2008) and was found in a family with primary immunodeficiency disease that had alternate molecular mechanism (Stray-Pedersen_2017). Taken together, this variant is classified as benign. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 28, 2016	- -

X-linked agammaglobulinemia with growth hormone deficiency Benign:2

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

X-linked agammaglobulinemia Benign:2

Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

X-linked agammaglobulinemia;C0472813:X-linked agammaglobulinemia with growth hormone deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jun 23, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.1
DANN	Benign	0.73

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

Other links and lift over

dbSNP: rs138411530; hg19: chrX-100630121;