X-101375202-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000061.3(BTK):c.83G>A(p.Arg28His) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,783 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. R28P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

BTK
NM_000061.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.54

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

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, 0.98

PP5

Variant X-101375202-C-T is Pathogenic according to our data. Variant chrX-101375202-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101375202-C-T is described in Lovd as [Pathogenic]. Variant chrX-101375202-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-101375202-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3 link	c.83G>A	p.Arg28His	missense_variant	Exon 2 of 19	ENST00000308731.8	NP_000052.1	Q06187-1Q5JY90
BTK	NM_001287344.2 link	c.185G>A	p.Arg62His	missense_variant	Exon 2 of 19		NP_001274273.1	Q06187-2
BTK	NM_001287345.2 link	c.83G>A	p.Arg28His	missense_variant	Exon 3 of 17		NP_001274274.1	Q06187Q5JY90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8 link	c.83G>A	p.Arg28His	missense_variant	Exon 2 of 19	1	NM_000061.3	ENSP00000308176.8		Q06187-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097783

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363143

show subpopulations

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked agammaglobulinemia

Pathogenic:3

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011348). Different missense changes at the same codon (p.Arg28Cys, p.Arg28Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000946996, VCV001075550). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jul 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 21, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderated, PM2 moderated, PP3 supporting -

not provided

Pathogenic:2

Sep 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with significantly impaired binding activity in comparison to wild-type (PMID: 8939985); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18518992, 19904586, 11668622, 9143921, 12655572, 8162018, 9030858, 15024743, 10859027, 27593100, 27512878, 9445504, 7849006, 8090769, 29424453, 29202590, 30290665, 11445810, 31378960, 32552675, 32888943, 36790564, 33584693, 38971313, 37063907, 39404906, 8939985) -

Autosomal recessive agammaglobulinemia 1

Pathogenic:1

Mar 13, 2007

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

X-linked agammaglobulinemia with growth hormone deficiency

Pathogenic:1

Nov 11, 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 28 of the BTK protein (p.Arg28His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked agammaglobulinemia (PMID: 9143921, 11668622, 19904586). This variant is also known as 215G>A. ClinVar contains an entry for this variant (Variation ID: 11348). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BTK protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BTK function (PMID: 8939985). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.65

BayesDel_noAF

Pathogenic

0.70

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

D;.;.;D

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.97

D;D;D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

.;.;.;M

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-4.3

.;D;.;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

.;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;.;D

Vest4

0.80

MutPred

0.91

Loss of MoRF binding (P = 0.008);Loss of MoRF binding (P = 0.008);.;Loss of MoRF binding (P = 0.008);

MVP

1.0

MPC

2.8

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over