X-101349664-C-A

Variant names:

• chrX-101349664-C-A
• rs1122765
• NM_000061.3:c.*221G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000061.3(BTK):​c.*221G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 421,263 control chromosomes in the GnomAD database, including 6 homozygotes. There are 120 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0032 (4 hom., 91 hem., cov: 22)
  • Exomes 𝑓: 0.00043 (2 hom. 29 hem.)
• Consequence: BTK NM_000061.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.190
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS2: High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.*221G>T		3_prime_UTR_variant	Exon 19 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.*221G>T		3_prime_UTR_variant	Exon 19 of 19		NP_001274273.1
BTK	NM_001287345.2	c.*221G>T		3_prime_UTR_variant	Exon 17 of 17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.*221G>T		3_prime_UTR_variant	Exon 19 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 352 AN: 111336 Hom.: 4 Cov.: 22

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000578

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000378

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000670

GnomAD4 exome AF: 0.000426 AC: 132 AN: 309873 Hom.: 2 Cov.: 3 AF XY: 0.000302 AC XY: 29 AN XY: 95871

African (AFR) AF: 0.0119 AC: 117 AN: 9802

American (AMR) AF: 0.000702 AC: 10 AN: 14250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9405

East Asian (EAS) AF: 0.00 AC: 0 AN: 23756

South Asian (SAS) AF: 0.00 AC: 0 AN: 20793

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23495

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1486

European-Non Finnish (NFE) AF: 0.00000532 AC: 1 AN: 188044

Other (OTH) AF: 0.000212 AC: 4 AN: 18842

GnomAD4 genome AF: 0.00316 AC: 352 AN: 111390 Hom.: 4 Cov.: 22 AF XY: 0.00271 AC XY: 91 AN XY: 33592

African (AFR) AF: 0.0112 AC: 344 AN: 30618

American (AMR) AF: 0.000578 AC: 6 AN: 10389

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3565

South Asian (SAS) AF: 0.000380 AC: 1 AN: 2635

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5956

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53163

Other (OTH) AF: 0.000662 AC: 1 AN: 1511

Alfa AF: 0.00167 Hom.: 48

Bravo AF: 0.00359

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

X-linked agammaglobulinemia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.74
PhyloP100		-0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1122765; hg19: chrX-100604652;