X-101353935-C-T

Variant names:

• chrX-101353935-C-T
• NM_000061.3:c.1685G>A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000061.3(BTK):​c.1685G>A​(p.Arg562Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R562P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.13

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000061.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101353935-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant X-101353935-C-T is Pathogenic according to our data. Variant chrX-101353935-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2431408.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.1685G>A	p.Arg562Gln	missense_variant	Exon 17 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.1787G>A	p.Arg596Gln	missense_variant	Exon 17 of 19		NP_001274273.1
BTK	NM_001287345.2	c.1157G>A	p.Arg386Gln	missense_variant	Exon 15 of 17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.1685G>A	p.Arg562Gln	missense_variant	Exon 17 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked agammaglobulinemia Pathogenic:1

Mar 30, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PM2 moderated, PM5 moderated, PP2 supporting, PP3 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D;.;.;D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.9	.;.;.;L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.2	.;N;.;N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0090	.;D;.;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.85
MutPred		0.88		Gain of ubiquitination at K558 (P = 0.0641);.;.;Gain of ubiquitination at K558 (P = 0.0641);
MVP		0.99
MPC		2.6
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-100608923; COSMIC: COSV58120218; COSMIC: COSV58120218;