X-101349957-C-T

Variant names:

• chrX-101349957-C-T
• NM_000061.3:c.1909-1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_000061.3(BTK):​c.1909-1G>A variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: BTK NM_000061.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.65
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.2560606 fraction of the gene.
• PM2: Very rare variant in population databases, with high coverage

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.1909-1G>A		splice_acceptor intron	N/A	NP_000052.1	Q06187-1
	BTK	NM_001287344.2		c.2011-1G>A		splice_acceptor intron	N/A	NP_001274273.1	Q06187-2
	BTK	NM_001287345.2		c.1381-1G>A		splice_acceptor intron	N/A	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.1909-1G>A		splice_acceptor intron	N/A	ENSP00000308176.8	Q06187-1
	BTK	ENST00000621635.4	TSL:1	c.2011-1G>A		splice_acceptor intron	N/A	ENSP00000483570.1	Q06187-2
	BTK	ENST00000944957.1		c.1990-1G>A		splice_acceptor intron	N/A	ENSP00000615016.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	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	0.32
CADD	Pathogenic	31
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		5.7
GERP RS		5.1
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -8
DS_AL_spliceai		0.98		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chrX-100604945;