NM_000061.3:c.1741T>C

Variant names:

• chrX-101353879-A-G
• rs128621205
• NM_000061.3:c.1741T>C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_000061.3(BTK):​c.1741T>C​(p.Trp581Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.27

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 11 ACMG points.

• PM1: In a helix (size 15) in uniprot entity BTK_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000061.3
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.995
• PP5: Variant X-101353879-A-G is Pathogenic according to our data. Variant chrX-101353879-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 11384.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-101353879-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.1741T>C	p.Trp581Arg	missense_variant	Exon 17 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.1843T>C	p.Trp615Arg	missense_variant	Exon 17 of 19		NP_001274273.1
BTK	NM_001287345.2	c.1213T>C	p.Trp405Arg	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.1741T>C	p.Trp581Arg	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: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked agammaglobulinemia Pathogenic:2

Oct 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Trp581Arg variant substitutes the tryptophan with an arginine at amino acid position 581 in the kinase domain. This variant has been reported in the medical literature in several unrelated individuals with X-linked agammaglobulinemia (XLA; MIM: 3000755; PMID: 7849697, PMID: 12655572). The tryptophan at amino acid 581 is conserved in the BTK protein and most other serine/threonine kinases. Other missense changes at this amino acid position (p.Trp581Cys, p.Trp581Ser) have also been reported in affected individuals (PMID: 25777788, PMID: 16405441). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.2	.;.;H
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-13	D;.;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.96		.;.;Gain of disorder (P = 0.0278);
MVP		1.0
MPC		3.5
ClinPred		1.0	D
GERP RS		5.5
Varity_R		1.0
gMVP		1.0

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: rs128621205; hg19: chrX-100608867;