chrX-101349783-AG-A

Variant names:

• chrX-101349783-AG-A
• rs1385972271
• NM_000061.3:c.*101delC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000061.3(BTK):​c.*101delC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 699,423 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000015 (0 hom. 2 hem.)
• Consequence: BTK NM_000061.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.416
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.*101delC		3_prime_UTR_variant	Exon 19 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.*101delC		3_prime_UTR_variant	Exon 19 of 19		NP_001274273.1
BTK	NM_001287345.2	c.*101delC		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.*101delC		3_prime_UTR_variant	Exon 19 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes AF: 0.00000898 AC: 1 AN: 111321 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000153 AC: 9 AN: 588102 Hom.: 0 Cov.: 9 AF XY: 0.0000114 AC XY: 2 AN XY: 175992

African (AFR) AF: 0.00 AC: 0 AN: 15663

American (AMR) AF: 0.000297 AC: 9 AN: 30293

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15072

East Asian (EAS) AF: 0.00 AC: 0 AN: 27718

South Asian (SAS) AF: 0.00 AC: 0 AN: 40452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39247

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3125

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 387585

Other (OTH) AF: 0.00 AC: 0 AN: 28947

GnomAD4 genome AF: 0.00000898 AC: 1 AN: 111321 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33519

African (AFR) AF: 0.00 AC: 0 AN: 30591

American (AMR) AF: 0.00 AC: 0 AN: 10389

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3549

South Asian (SAS) AF: 0.00 AC: 0 AN: 2657

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5963

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53104

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 11, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.*101delC in BTK gene is a deletion of conserved nucleotide in 3' UTR region. Mutation Taster algorithm predicts this change to not affect a poly(A) signal, however, no stability studies were published at the time of evaluation. The presence of the variant in the general population could not be determined at this time as this region is not covered the control population dataset of ExAC and has not, to our knowledge, been reported in affected individuals via published reports or by reputable databases/clinical laboratories. An internal subject (famale) carrying this variant also carried c.799_806delAACTATGTT (evaluated as likely pathogenic); however, phase of the variants are unknown. Taken together, the variant was classified as VUS. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42

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: rs1385972271; hg19: chrX-100604771;