rs35877704

chrX-101360729-C-AchrX-101360729-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.74

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, BTK
• 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].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00113 (126/111329) while in subpopulation NFE AF= 0.00169 (90/53105). AF 95% confidence interval is 0.00141. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 34 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTK	NM_000061.3	c.615G>T	p.Glu205Asp	missense_variant	8/19	ENST00000308731.8
BTK	NM_001287344.2	c.717G>T	p.Glu239Asp	missense_variant	8/19
BTK	NM_001287345.2	c.615G>T	p.Glu205Asp	missense_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTK	ENST00000308731.8	c.615G>T	p.Glu205Asp	missense_variant	8/19	1	NM_000061.3	P3

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 126 AN: 111275 Hom.: 0 Cov.: 22 AF XY: 0.00102 AC XY: 34 AN XY: 33461

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.: 0 AF XY: 0.000900 AC XY: 61 AN XY: 67758

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.: 1 Cov.: 32 AF XY: 0.00172 AC XY: 624 AN XY: 363542

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.: 0 Cov.: 22 AF XY: 0.00101 AC XY: 34 AN XY: 33525

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.: 80

Bravo AF: 0.000982

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00223 AC: 15

ExAC AF: 0.00105 AC: 128

EpiCase AF: 0.00196

EpiControl AF: 0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 02, 2016	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 -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2015	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. -

X-linked agammaglobulinemia with growth hormone deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 16, 2017	- -

BTK-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2020

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 05, 2022

- -

X-linked agammaglobulinemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;.;T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0062	T;T;T;T
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.52	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	T
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

Other links and lift over

dbSNP: rs35877704; hg19: chrX-100615717; COSMIC: COSV58121072; COSMIC: COSV58121072;