Genetic Variant BTK:p.Met655Ile (chrX-101349900-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM1PP2BP4_ModerateBP6_ModerateBS2

The NM_000061.3(BTK):c.1965G>A(p.Met655Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,095,952 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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: not found (cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 2 hem. )

Consequence

BTK
NM_000061.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.22

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 Likely_benign. Variant got -5 ACMG points.

PM1

In a domain Protein kinase (size 253) in uniprot entity BTK_HUMAN there are 43 pathogenic changes around while only 1 benign (98%) in NM_000061.3

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=0.15746889).

BP6

Variant X-101349900-C-T is Benign according to our data. Variant chrX-101349900-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3636307.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3 link	c.1965G>A	p.Met655Ile	missense_variant	Exon 19 of 19	ENST00000308731.8	NP_000052.1	Q06187-1Q5JY90
BTK	NM_001287344.2 link	c.2067G>A	p.Met689Ile	missense_variant	Exon 19 of 19		NP_001274273.1	Q06187-2
BTK	NM_001287345.2 link	c.1437G>A	p.Met479Ile	missense_variant	Exon 17 of 17		NP_001274274.1	Q06187Q5JY90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8 link	c.1965G>A	p.Met655Ile	missense_variant	Exon 19 of 19	1	NM_000061.3	ENSP00000308176.8		Q06187-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183449

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67879

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000105

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1095952

Hom.:

Cov.:

AF XY:

0.00000553

AC XY:

AN XY:

361382

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:

0.0000370

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency

Benign:1

Mar 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

.;.;T

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.029

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.57

.;.;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.93

N;.;N

REVEL

Benign

0.20

Sift

Pathogenic

0.0

D;.;T

Sift4G

Benign

0.44

T;T;T

Polyphen

0.011

B;.;B

Vest4

0.21

MutPred

0.26

.;.;Loss of loop (P = 0.1242);

MVP

0.90

MPC

1.4

ClinPred

0.28

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.83

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