chrX-101356060-G-C

Position:

• chrX-101356060-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_000061.3(BTK):​c.1558C>G​(p.Arg520Gly) variant causes a missense 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.70

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 11 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, 0.993
• PP5: Variant X-101356060-G-C is Pathogenic according to our data. Variant chrX-101356060-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 530948.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-101356060-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTK	NM_000061.3	c.1558C>G	p.Arg520Gly	missense_variant	15/19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.1660C>G	p.Arg554Gly	missense_variant	15/19		NP_001274273.1
BTK	NM_001287345.2	c.1039-1366C>G		intron_variant			NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.1558C>G	p.Arg520Gly	missense_variant	15/19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 13, 2018

This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with X-linked agammaglobulinemia (PMID: 12655572). This variant is also known as c.1690C>G in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Arg520Gln) has been determined to be pathogenic (PMID: 12655572, 7849721, 11472359, 7880320, 12217331, 15661032, 18677443, 27980540). This suggests that the arginine residue is critical for BTK protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces arginine with glycine at codon 520 of the BTK protein (p.Arg520Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;D
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	2.9	.;.;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.9	.;.;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.99
MutPred		0.97		Gain of catalytic residue at R520 (P = 0.0208);.;Gain of catalytic residue at R520 (P = 0.0208);
MVP		1.0
MPC		2.9
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs128621201; hg19: chrX-100611048;