chrX-101360729-C-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_000061.3(BTK):c.615G>T(p.Glu205Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,209,517 control chromosomes in the GnomAD database, including 1 homozygotes. There are 658 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., 34 hem., cov: 22)

Exomes 𝑓: 0.0018 ( 1 hom. 624 hem. )

Consequence

BTK
NM_000061.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.74

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 Benign. Variant got -15 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061905086).

BP6

Variant X-101360729-C-A is Benign according to our data. Variant chrX-101360729-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 286327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101360729-C-A is described in Lovd as [Likely_benign]. Variant chrX-101360729-C-A is described in Lovd as [Pathogenic].

BS2

High Hemizygotes in GnomAd4 at 34 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3 link	c.615G>T	p.Glu205Asp	missense_variant	Exon 8 of 19	ENST00000308731.8	NP_000052.1	Q06187-1Q5JY90
BTK	NM_001287344.2 link	c.717G>T	p.Glu239Asp	missense_variant	Exon 8 of 19		NP_001274273.1	Q06187-2
BTK	NM_001287345.2 link	c.615G>T	p.Glu205Asp	missense_variant	Exon 9 of 17		NP_001274274.1	Q06187Q5JY90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8 link	c.615G>T	p.Glu205Asp	missense_variant	Exon 8 of 19	1	NM_000061.3	ENSP00000308176.8		Q06187-1

Frequencies

GnomAD3 genomes

AF:

0.00113

AC:

126

AN:

111275

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

33461

show subpopulations

Gnomad AFR

AF:

0.000295

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000288

Gnomad ASJ

AF:

0.00719

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00169

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00110

AC:

202

AN:

183290

Hom.:

AF XY:

0.000900

AC XY:

AN XY:

67758

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.000401

Gnomad ASJ exome

AF:

0.00628

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000472

Gnomad FIN exome

AF:

0.000250

Gnomad NFE exome

AF:

0.00147

Gnomad OTH exome

AF:

0.00221

GnomAD4 exome

AF:

0.00181

AC:

1985

AN:

1098188

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

624

AN XY:

363542

show subpopulations

Gnomad4 AFR exome

AF:

0.000341

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.00645

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000332

Gnomad4 FIN exome

AF:

0.000247

Gnomad4 NFE exome

AF:

0.00207

Gnomad4 OTH exome

AF:

0.00139

GnomAD4 genome

AF:

0.00113

AC:

126

AN:

111329

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

33525

show subpopulations

Gnomad4 AFR

AF:

0.000294

Gnomad4 AMR

AF:

0.000288

Gnomad4 ASJ

AF:

0.00719

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00169

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00180

Hom.:

Bravo

AF:

0.000982

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00223

AC:

ExAC

AF:

0.00105

AC:

128

EpiCase

AF:

0.00196

EpiControl

AF:

0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Aug 24, 2015

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 01, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 0.1% in ExAC , 30 hemizygotes -

not provided

Benign:3

Aug 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 16, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

X-linked agammaglobulinemia with growth hormone deficiency

Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

BTK-related disorder

Benign:1

Feb 24, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

X-linked agammaglobulinemia;C0472813:X-linked agammaglobulinemia with growth hormone deficiency

Benign:1

May 05, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

X-linked agammaglobulinemia

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;.;.;T

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.79

T;T;T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.0062

T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.0

.;.;.;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.54

.;N;.;N

REVEL

Benign

0.15

Sift

Benign

0.59

.;T;.;T

Sift4G

Benign

0.62

T;T;T;T

Polyphen

0.33, 0.084

.;B;.;B

Vest4

0.036

MutPred

0.36

Loss of glycosylation at P203 (P = 0.1191);Loss of glycosylation at P203 (P = 0.1191);.;Loss of glycosylation at P203 (P = 0.1191);

MVP

0.85

MPC

1.2

ClinPred

0.020

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.64

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