X-101349943-C-T

Variant names:

• chrX-101349943-C-T
• rs1926220192
• NM_000061.3:c.1922G>A

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.1922G>A​(p.Arg641His) variant causes a missense change. The variant allele was found at a frequency of 0.000000916 in 1,092,254 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. R641C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.65

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 19 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
• 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 the BTK gene, where missense mutations are typically associated with disease (based on misZ statistic). 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). GenCC associations: The gene is linked to 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-101349943-C-T is Pathogenic according to our data. Variant chrX-101349943-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 988456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101349943-C-T is described in Lovd as [Pathogenic]. Variant chrX-101349943-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.1922G>A	p.Arg641His	missense_variant	Exon 19 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.2024G>A	p.Arg675His	missense_variant	Exon 19 of 19		NP_001274273.1
BTK	NM_001287345.2	c.1394G>A	p.Arg465His	missense_variant	Exon 17 of 17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.1922G>A	p.Arg641His	missense_variant	Exon 19 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.16e-7 AC: 1 AN: 1092254 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 357760

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000120

Gnomad4 OTH exome AF: 0.00

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

May 26, 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 histidine, which is basic and polar, at codon 641 of the BTK protein (p.Arg641His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked agammaglobulinemia (PMID: 7633420, 17765309). ClinVar contains an entry for this variant (Variation ID: 988456). 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 Pathogenic:1

Nov 05, 2014

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.78
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;.;D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	5.2	.;.;H
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.1	D;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.90
MutPred		0.98		.;.;Loss of ubiquitination at K637 (P = 0.0863);
MVP		1.0
MPC		2.8
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs1926220192; hg19: chrX-100604931; COSMIC: COSV58118855; COSMIC: COSV58118855;