chrX-101354676-CCAAA-C

Variant names:

• chrX-101354676-CCAAA-C
• rs1555977592
• NM_000061.3:c.1581_1584delTTTG

Variant summary

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

The NM_001287344.2(BTK):​c.1683_1686delTTTG​(p.Cys561TrpfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: BTK NM_001287344.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.39
• Publications: 3 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: ClinGen, Labcorp Genetics (formerly Invitae)
• 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-101354676-CCAAA-C is Pathogenic according to our data. Variant chrX-101354676-CCAAA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 492818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001287344.2. 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.1581_1584delTTTG	p.Cys527TrpfsTer2	frameshift	Exon 16 of 19	NP_000052.1
	BTK	NM_001287344.2		c.1683_1686delTTTG	p.Cys561TrpfsTer2	frameshift	Exon 16 of 19	NP_001274273.1
	BTK	NM_001287345.2		c.1053_1056delTTTG	p.Cys351TrpfsTer2	frameshift	Exon 14 of 17	NP_001274274.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTK	ENST00000308731.8	TSL:1 MANE Select	c.1581_1584delTTTG	p.Cys527TrpfsTer2	frameshift	Exon 16 of 19	ENSP00000308176.8
	BTK	ENST00000621635.4	TSL:1	c.1683_1686delTTTG	p.Cys561TrpfsTer2	frameshift	Exon 16 of 19	ENSP00000483570.1
	BTK	ENST00000944957.1		c.1662_1665delTTTG	p.Cys554TrpfsTer2	frameshift	Exon 16 of 19	ENSP00000615016.1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive agammaglobulinemia 1 (1)
1	-	-	not provided (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
PhyloP100		7.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1555977592; hg19: chrX-100609664;