rs128620187

Variant names:

• chrX-101375248-G-A
• rs128620187
• NM_000061.3:c.37C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-101375248-G-A
• chrX-101375248-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000061.3(BTK):​c.37C>T​(p.Arg13*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R13R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: BTK NM_000061.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.62
• Publications: 6 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 273 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-101375248-G-A is Pathogenic according to our data. Variant chrX-101375248-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.37C>T	p.Arg13*	stop_gained	Exon 2 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.139C>T	p.Arg47*	stop_gained	Exon 2 of 19		NP_001274273.1
BTK	NM_001287345.2	c.37C>T	p.Arg13*	stop_gained	Exon 3 of 17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.37C>T	p.Arg13*	stop_gained	Exon 2 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked agammaglobulinemia Pathogenic:3

Apr 29, 2025

Next Generation Genetic Polyclinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pathogenic missense variant in BTK gene (NM_000061.3:c.37C>T), identified through clinical testing. This germline alteration results in a hemizygous substitution affecting exon 2 of the BTK gene, consistent with X-linked recessive inheritance. It has been well-documented in association with X-linked agammaglobulinemia and is classified as pathogenic based on multiple lines of evidence. Sanger sequencing confirmed variant presence. The variant is expected to disrupt protein function and is supported by prior reports in ClinVar and scientific literature. Meets ACMG criteria including PS1, PM2, PP3, and PP5 (if applicable). -

Oct 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

X-linked agammaglobulinemia with growth hormone deficiency Pathogenic:1

Apr 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg13*) in the BTK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BTK are known to be pathogenic (PMID: 15661032, 16862044, 19419768). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with X-linked recessive agammaglobulinemia (PMID: 7849697). ClinVar contains an entry for this variant (Variation ID: 11344). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		2.6
Vest4		0.97
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs128620187; hg19: chrX-100630236; COSMIC: COSV58118363;