X-101349541-CCA-C

Variant names:

• chrX-101349541-CCA-C
• rs200445244
• NM_000061.3:c.*342_*343delTG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000061.3(BTK):​c.*342_*343delTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.035 in 226,054 control chromosomes in the GnomAD database, including 152 homozygotes. There are 2,028 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (72 hom., 920 hem., cov: 21)
  • Exomes 𝑓: 0.037 (80 hom. 1108 hem.)
• Consequence: BTK NM_000061.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.224
• 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: 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 -10 ACMG points.

• BP6: Variant X-101349541-CCA-C is Benign according to our data. Variant chrX-101349541-CCA-C is described in ClinVar as [Likely_benign]. Clinvar id is 367690.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0325 (3597/110646) while in subpopulation NFE AF = 0.051 (2697/52855). AF 95% confidence interval is 0.0494. There are 72 homozygotes in GnomAd4. There are 920 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 72 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.*342_*343delTG		3_prime_UTR_variant	Exon 19 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.*342_*343delTG		3_prime_UTR_variant	Exon 19 of 19		NP_001274273.1
BTK	NM_001287345.2	c.*342_*343delTG		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.*342_*343delTG		3_prime_UTR_variant	Exon 19 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 3597 AN: 110595 Hom.: 72 Cov.: 21

Gnomad AFR AF: 0.00623

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.0239

Gnomad ASJ AF: 0.0212

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00491

Gnomad FIN AF: 0.0452

Gnomad MID AF: 0.00431

Gnomad NFE AF: 0.0510

Gnomad OTH AF: 0.0295

GnomAD4 exome AF: 0.0374 AC: 4312 AN: 115408 Hom.: 80 AF XY: 0.0388 AC XY: 1108 AN XY: 28584

African (AFR) AF: 0.00779 AC: 37 AN: 4750

American (AMR) AF: 0.0186 AC: 95 AN: 5100

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 116 AN: 4789

East Asian (EAS) AF: 0.000171 AC: 2 AN: 11715

South Asian (SAS) AF: 0.0104 AC: 37 AN: 3570

European-Finnish (FIN) AF: 0.0417 AC: 149 AN: 3572

Middle Eastern (MID) AF: 0.00375 AC: 2 AN: 533

European-Non Finnish (NFE) AF: 0.0489 AC: 3571 AN: 72997

Other (OTH) AF: 0.0361 AC: 303 AN: 8382

GnomAD4 genome AF: 0.0325 AC: 3597 AN: 110646 Hom.: 72 Cov.: 21 AF XY: 0.0280 AC XY: 920 AN XY: 32890

African (AFR) AF: 0.00621 AC: 189 AN: 30420

American (AMR) AF: 0.0239 AC: 247 AN: 10333

Ashkenazi Jewish (ASJ) AF: 0.0212 AC: 56 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3545

South Asian (SAS) AF: 0.00493 AC: 13 AN: 2638

European-Finnish (FIN) AF: 0.0452 AC: 263 AN: 5815

Middle Eastern (MID) AF: 0.00474 AC: 1 AN: 211

European-Non Finnish (NFE) AF: 0.0510 AC: 2697 AN: 52855

Other (OTH) AF: 0.0291 AC: 44 AN: 1511

Alfa AF: 0.0135 Hom.: 61

Bravo AF: 0.0302

Asia WGS AF: 0.00438 AC: 11 AN: 2522

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked agammaglobulinemia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Isolated congenital growth hormone deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

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: rs200445244; hg19: chrX-100604529;