chrX-101370018-C-T

Variant names:

• chrX-101370018-C-T
• rs1555980049
• NM_000061.3:c.371G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000061.3(BTK):​c.371G>A​(p.Trp124*) variant causes a stop gained 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: BTK NM_000061.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.01
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), ClinGen
• short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-101370018-C-T is Pathogenic according to our data. Variant chrX-101370018-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 492811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000061.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTK	NM_000061.3	MANE Select	c.371G>A	p.Trp124*	stop_gained	Exon 5 of 19	NP_000052.1	Q06187-1
	BTK	NM_001287344.2		c.473G>A	p.Trp158*	stop_gained	Exon 5 of 19	NP_001274273.1	Q06187-2
	BTK	NM_001287345.2		c.371G>A	p.Trp124*	stop_gained	Exon 6 of 17	NP_001274274.1	Q5JY90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTK	ENST00000308731.8	TSL:1 MANE Select	c.371G>A	p.Trp124*	stop_gained	Exon 5 of 19	ENSP00000308176.8	Q06187-1
	BTK	ENST00000621635.4	TSL:1	c.473G>A	p.Trp158*	stop_gained	Exon 5 of 19	ENSP00000483570.1	Q06187-2
	BTK	ENST00000944957.1		c.371G>A	p.Trp124*	stop_gained	Exon 5 of 19	ENSP00000615016.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive agammaglobulinemia 1 (1)
1	-	-	X-linked agammaglobulinemia (1)
1	-	-	X-linked agammaglobulinemia with growth hormone deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.0
Vest4		0.99
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs1555980049; hg19: chrX-100625006; COSMIC: COSV58124122; COSMIC: COSV58124122;