rs128621203

Positions:

• chrX-101354636-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000061.3(BTK):​c.1625T>C​(p.Leu542Pro) variant causes a missense change involving the alteration of a 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.39

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain Protein kinase (size 253) in uniprot entity BTK_HUMAN there are 43 pathogenic changes around while only 1 benign (98%) in NM_000061.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BTK. . Gene score misZ 4.0394 (greater than the threshold 3.09). GenCC has associacion of gene with short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia, Bruton-type agammaglobulinemia, isolated growth hormone deficiency type III.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-101354636-A-G is Pathogenic according to our data. Variant chrX-101354636-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 11381.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chrX-101354636-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTK	NM_000061.3	c.1625T>C	p.Leu542Pro	missense_variant	16/19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.1727T>C	p.Leu576Pro	missense_variant	16/19		NP_001274273.1
BTK	NM_001287345.2	c.1097T>C	p.Leu366Pro	missense_variant	14/17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.1625T>C	p.Leu542Pro	missense_variant	16/19	1	NM_000061.3	ENSP00000308176	P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 542 of the BTK protein (p.Leu542Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked agammaglobulinemia (PMID: 7849697, 12655572). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11381). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BTK protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 03, 2019

The BTK c.1625T>C; p.Leu542Pro variant (rs128621203) is reported in the literature in individuals affected with X-linked agammaglobulinemia (Conley 1994, Danielian 2003). This variant is reported in ClinVar (Variation ID: 11381), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 542 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Structural analyses of the BTK protein show that leucine 542 may be important for substrate binding (Mattsson 1996). However, given the limited amount of clinical data and lack of functional data, the significance of the p.Leu542Pro variant is uncertain at this time. References: Conley et al. Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase. Hum Mol Genet. 1994 Oct;3(10):1751-6. Danielian S et al. Bruton tyrosine kinase gene mutations in Argentina. Hum Mutat. 2003 Apr;21(4):451. Mattsson PT et al. X-linked agammaglobulinemia (XLA): a genetic tyrosine kinase (Btk) disease. Bioessays. 1996 Oct;18(10):825-34. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	.;.;.;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.5	.;D;.;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	.;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0, 0.93	.;D;.;P
Vest4		0.95
MutPred		0.95		Gain of disorder (P = 0.0522);.;.;Gain of disorder (P = 0.0522);
MVP		1.0
MPC		3.3
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		1.0

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: rs128621203; hg19: chrX-100609624;