X-101360624-T-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_000061.3(BTK):c.720A>C(p.Glu240Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000562 in 1,210,003 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000056 ( 0 hom. 16 hem. )

Consequence

BTK
NM_000061.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.38

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

Bruton-type agammaglobulinemia
Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, ClinGen
isolated growth hormone deficiency type III
Inheritance: XL Classification: STRONG, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

BTK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. 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). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Bruton-type agammaglobulinemia, short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia, isolated growth hormone deficiency type III.

BP4

Computational evidence support a benign effect (MetaRNN=0.2804863).

BS2

High Hemizygotes in GnomAdExome4 at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
BTK	NM_000061.3 link	c.720A>C	p.Glu240Asp	missense_variant	Exon 8 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2 link	c.822A>C	p.Glu274Asp	missense_variant	Exon 8 of 19		NP_001274273.1
BTK	NM_001287345.2 link	c.720A>C	p.Glu240Asp	missense_variant	Exon 9 of 17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8 link	c.720A>C	p.Glu240Asp	missense_variant	Exon 8 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes

AF:

0.0000537

AC:

AN:

111778

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000373

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000752

Gnomad OTH

AF:

0.000666

GnomAD2 exomes

AF:

0.0000600

AC:

AN:

183419

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000721

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000733

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000565

AC:

AN:

1098225

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

363579

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26401

American (AMR)

AF:

0.0000568

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19386

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54149

European-Finnish (FIN)

AF:

0.0000493

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000629

AC:

AN:

842110

Other (OTH)

AF:

0.0000434

AC:

AN:

46097

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000537

AC:

AN:

111778

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33944

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30707

American (AMR)

AF:

0.00

AC:

AN:

10484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3564

South Asian (SAS)

AF:

0.000373

AC:

AN:

2678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6111

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000752

AC:

AN:

53167

Other (OTH)

AF:

0.000666

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000497

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

BTK-related disorder

Uncertain:1

Oct 12, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BTK c.720A>C variant is predicted to result in the amino acid substitution p.Glu240Asp. This variant has been reported in an individual with X-linked agammaglobulinemia, however there was no conclusion regarding pathogenicity of this variant (Abbott et al. 2013. PubMed ID: 24001798). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD, including two hemizygous individuals (http://gnomad.broadinstitute.org/variant/X-100615612-T-G). While this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

X-linked agammaglobulinemia with growth hormone deficiency

Uncertain:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 240 of the BTK protein (p.Glu240Asp). This variant is present in population databases (rs141590686, gnomAD 0.009%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with BTK-related conditions. ClinVar contains an entry for this variant (Variation ID: 461818). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

X-linked agammaglobulinemia

Uncertain:1

May 26, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0109 - This gene is known to be associated with X-linked recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a glutamic acid to an aspartic acid (exon 8). (N) 0253 - Variant is hemizygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes, 2 hemizygotes). (P) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (N) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region) (SH3 domain; PMID: 24001798, NCBI, Decipher, PDB). (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are inconclusive. This variant has been previously reported as VUS (ClinVar). In addition, it has been reported in a patient with X-linked agammaglobulinemia, however, there was no conclusion regarding pathogenicity. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;.;.;D

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.83

T;T;T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.4

.;.;.;M

PhyloP100

1.4

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.1

.;N;.;D

REVEL

Benign

0.18

Sift

Uncertain

0.018

.;D;.;D

Sift4G

Benign

0.067

T;T;T;T

Polyphen

0.056, 0.0010

.;B;.;B

Vest4

0.47

MutPred

0.37

Gain of ubiquitination at K237 (P = 0.0609);Gain of ubiquitination at K237 (P = 0.0609);.;Gain of ubiquitination at K237 (P = 0.0609);

MVP

0.80

MPC

1.2

ClinPred

0.11

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.82

gMVP

0.89

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over