rs128621194

Variant names:

• chrX-101359325-G-A
• rs128621194
• NM_000061.3:c.862C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000061.3(BTK):​c.862C>T​(p.Arg288Trp) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R288Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.33
• Publications: 16 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 19 ACMG points.

• PM1: In a domain SH2 (size 96) in uniprot entity BTK_HUMAN there are 17 pathogenic changes around while only 1 benign (94%) in NM_000061.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101359324-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 492813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 90 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 4.0394 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Bruton-type agammaglobulinemia, short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia, isolated growth hormone deficiency type III.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant X-101359325-G-A is Pathogenic according to our data. Variant chrX-101359325-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11366.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.862C>T	p.Arg288Trp	missense_variant	Exon 10 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.964C>T	p.Arg322Trp	missense_variant	Exon 10 of 19		NP_001274273.1
BTK	NM_001287345.2	c.862C>T	p.Arg288Trp	missense_variant	Exon 11 of 17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.862C>T	p.Arg288Trp	missense_variant	Exon 10 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

X-linked agammaglobulinemia Pathogenic:2

Oct 29, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011366, PMID:8162056, PS1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 15112668, 17765309, 14974089, PS4_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000492813, PMID:9545398, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.915, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

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

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BTK NM_000061.2 exon 10 p.Arg288Trp (c.862C>T): This variant has been reported in the literature in at least 3 individuals with X-linked agammaglobulinemia (XLA), segregating with disease in at least 5 affected family members (Mensink 1984 PMID:6595200, deWeers 1994 PMID:8162018, Bradley 1998 PMID:8162056, Kanegane 2001 PMID:11742281, Lopez-Herrera 2008 PMID:17765309). However, individuals from 1 family exhibited significant clinical and immunological heterogenity (Mensink 1984 PMID:6595200, deWeers 1994 PMID:8162018, Bradley 1998 PMID:8162056). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:11366). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies also predict that this variant will impact the protein (Tzeng 2000 PMID:11206059, Lopez-Herrera 2008 PMID:17765309). Of note, a different variant at this same codon (p.Arg288Gln) has been reported in the literature in individuals with disease, supporting that this region has significance. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic. -

X-linked agammaglobulinemia with growth hormone deficiency Pathogenic:1

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 288 of the BTK protein (p.Arg288Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked agammaglobulinemia (PMID: 14974089, 15112668, 17765309). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11366). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BTK protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BTK function (PMID: 11206059). This variant disrupts the p.Arg288 amino acid residue in BTK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9545398, 12217331, 15661032). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	.;.;.;H
PhyloP100		4.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.0	.;D;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.89
MutPred		0.85		Loss of disorder (P = 0.0174);Loss of disorder (P = 0.0174);.;Loss of disorder (P = 0.0174);
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.97
gMVP		0.99
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs128621194; hg19: chrX-100614313;