rs28935478

Positions:

• chrX-101358330-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_000061.3(BTK):​c.1082A>G​(p.Tyr361Cys) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.99

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 Likely_pathogenic. Variant got 9 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
• 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, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTK	NM_000061.3	c.1082A>G	p.Tyr361Cys	missense_variant	12/19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.1184A>G	p.Tyr395Cys	missense_variant	12/19		NP_001274273.1
BTK	NM_001287345.2	c.1038+44A>G		intron_variant			NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.1082A>G	p.Tyr361Cys	missense_variant	12/19	1	NM_000061.3	ENSP00000308176	P3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked agammaglobulinemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1994

- -

X-linked agammaglobulinemia with growth hormone deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 361 of the BTK protein (p.Tyr361Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with agammaglobulinemia (PMID: 7849697, 8164701). ClinVar contains an entry for this variant (Variation ID: 11346). 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%. Experimental studies have shown that this missense change affects BTK function (PMID: 10754312, 11206059). This variant disrupts the p.Tyr261 amino acid residue in BTK. Other variant(s) that disrupt this residue have been observed in individuals with BTK-related conditions (PMID: 15661032), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	.;.;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-8.7	.;.;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	.;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.81
MutPred		0.83		Loss of stability (P = 0.0807);.;Loss of stability (P = 0.0807);
MVP		1.0
MPC		2.8
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.98
gMVP		0.96

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: rs28935478; hg19: chrX-100613318;