rs1555980875

Positions:

• chrX-101375166-T-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000061.3(BTK):​c.119A>G​(p.Tyr40Cys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y40N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.63

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a modified_residue Phosphotyrosine (size 0) in uniprot entity BTK_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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, 0.982
• PP5: Variant X-101375166-T-C is Pathogenic according to our data. Variant chrX-101375166-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 449226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101375166-T-C is described in Lovd as [Pathogenic]. Variant chrX-101375166-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTK	NM_000061.3	c.119A>G	p.Tyr40Cys	missense_variant	2/19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.221A>G	p.Tyr74Cys	missense_variant	2/19		NP_001274273.1
BTK	NM_001287345.2	c.119A>G	p.Tyr40Cys	missense_variant	3/17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.119A>G	p.Tyr40Cys	missense_variant	2/19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 26, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 40 of the BTK protein (p.Tyr40Cys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked agammaglobulinemia (PMID: 8695804, 9260159, 12204007, 28359783). This variant is also known as c.251A>G. ClinVar contains an entry for this variant (Variation ID: 449226). 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. Studies have shown that this missense change results in the emergence of a cryptic splice site resulting in a 23-base deletion in exon 2 and introduces a premature termination codon (PMID: 8695804, 12204007, 28359783). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2017

The Y40C variant has been published previously in association with X-linked agammaglobulinemia (Kanegane et al., 2001; Tani et al., 2002; Lee et al., 2010; Chen et al., 2016). It has also been observed in an affected individual tested at GeneDx. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Y40C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	2.9	.;.;.;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.4	.;D;.;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	.;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.92
MutPred		0.85		Loss of ubiquitination at K36 (P = 0.1062);Loss of ubiquitination at K36 (P = 0.1062);.;Loss of ubiquitination at K36 (P = 0.1062);
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: 1
DS_DL_spliceai		0.82		Position offset: -22

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555980875; hg19: chrX-100630154;