rs782702231

chrX-101349965-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000061.3(BTK):c.1909-9T>C variant causes a splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.000655 in 1,180,184 control chromosomes in the GnomAD database, including 1 homozygotes. There are 226 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., 8 hem., cov: 22)
  • Exomes 𝑓: 0.00069 (1 hom. 218 hem.)
• Consequence: BTK NM_000061.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.02493
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 6.27

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-101349965-A-G is Benign according to our data. Variant chrX-101349965-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194911.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000279 (31/111197) while in subpopulation NFE AF= 0.000452 (24/53069). AF 95% confidence interval is 0.000312. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTK	NM_000061.3	c.1909-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000308731.8
BTK	NM_001287344.2	c.2011-9T>C		splice_polypyrimidine_tract_variant, intron_variant
BTK	NM_001287345.2	c.1381-9T>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTK	ENST00000308731.8	c.1909-9T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000061.3	P3

Frequencies

GnomAD3 genomes AF: 0.000279 AC: 31 AN: 111143 Hom.: 0 Cov.: 22 AF XY: 0.000240 AC XY: 8 AN XY: 33301

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000338

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000452

Gnomad OTH AF: 0.000670

GnomAD3 exomes AF: 0.000295 AC: 54 AN: 182780 Hom.: 0 AF XY: 0.000341 AC XY: 23 AN XY: 67476

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.000314

Gnomad NFE exome AF: 0.000492

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000694 AC: 742 AN: 1068987 Hom.: 1 Cov.: 27 AF XY: 0.000648 AC XY: 218 AN XY: 336445

Gnomad4 AFR exome AF: 0.000116

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000112

Gnomad4 FIN exome AF: 0.000568

Gnomad4 NFE exome AF: 0.000845

Gnomad4 OTH exome AF: 0.000443

GnomAD4 genome AF: 0.000279 AC: 31 AN: 111197 Hom.: 0 Cov.: 22 AF XY: 0.000240 AC XY: 8 AN XY: 33365

Gnomad4 AFR AF: 0.000131

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000338

Gnomad4 NFE AF: 0.000452

Gnomad4 OTH AF: 0.000661

Alfa AF: 0.000364 Hom.: 3

Bravo AF: 0.000200

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 17, 2014

- -

X-linked agammaglobulinemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	20
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.025
dbscSNV1_RF	Benign	0.20
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

Publications

LitVar

Other links and lift over

dbSNP: rs782702231; hg19: chrX-100604953;