rs1386621585

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP2

The NM_000061.3(BTK):c.941A>G(p.Lys314Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000165 in 1,209,192 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

BTK
NM_000061.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.83

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 Uncertain_significance. Variant got 3 ACMG points.

PM1

In a domain SH2 (size 96) in uniprot entity BTK_HUMAN there are 31 pathogenic changes around while only 0 benign (100%) in NM_000061.3

PP2

Missense variant where missense usually causes diseases, BTK

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
BTK	NM_000061.3 linkuse as main transcript	c.941A>G	p.Lys314Arg	missense_variant	11/19	ENST00000308731.8
BTK	NM_001287344.2 linkuse as main transcript	c.1043A>G	p.Lys348Arg	missense_variant	11/19
BTK	NM_001287345.2 linkuse as main transcript	c.941A>G	p.Lys314Arg	missense_variant	12/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTK	ENST00000308731.8 linkuse as main transcript	c.941A>G	p.Lys314Arg	missense_variant	11/19	1	NM_000061.3	P3	Q06187-1

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111706

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33884

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000950

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097486

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362850

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:

0.00

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111706

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33884

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000950

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 314 of the BTK protein (p.Lys314Arg). This variant is not present in population databases (gnomAD no frequency). 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: 461819). 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 not expected to disrupt BTK protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

Cadd

Benign

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.46

T;.;.;D

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

T;D;T;T

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.52

D;D;D;D

MetaSVM

Uncertain

0.54

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.76

Sift4G

Benign

0.47

T;T;T;T

Polyphen

0.97, 1.0

.;D;.;D

Vest4

0.27

MutPred

0.25

Gain of MoRF binding (P = 0.0654);Gain of MoRF binding (P = 0.0654);.;Gain of MoRF binding (P = 0.0654);

MVP

0.97

MPC

2.4

ClinPred

0.81

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.48

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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