X-101349543-A-C

Variant names:

• chrX-101349543-A-C
• rs781937023
• NM_000061.3:c.*342T>G

Variant summary

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

The NM_000061.3(BTK):​c.*342T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 207,045 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., 8 hem., cov: 21)
  • Exomes 𝑓: 0.00021 (0 hom. 4 hem.)
• Consequence: BTK NM_000061.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.33
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.000298 AC: 31 AN: 103986 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000671

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000711

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000566

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000187

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000395

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000214 AC: 22 AN: 103007 Hom.: 0 Cov.: 0 AF XY: 0.000154 AC XY: 4 AN XY: 26047

African (AFR) AF: 0.000443 AC: 2 AN: 4519

American (AMR) AF: 0.00 AC: 0 AN: 4753

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4413

East Asian (EAS) AF: 0.00 AC: 0 AN: 11304

South Asian (SAS) AF: 0.00 AC: 0 AN: 3265

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 512

European-Non Finnish (NFE) AF: 0.000299 AC: 19 AN: 63594

Other (OTH) AF: 0.000133 AC: 1 AN: 7519

GnomAD4 genome AF: 0.000298 AC: 31 AN: 104038 Hom.: 0 Cov.: 21 AF XY: 0.000253 AC XY: 8 AN XY: 31630

African (AFR) AF: 0.0000669 AC: 2 AN: 29897

American (AMR) AF: 0.000710 AC: 7 AN: 9864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2546

East Asian (EAS) AF: 0.000567 AC: 2 AN: 3525

South Asian (SAS) AF: 0.00 AC: 0 AN: 2609

European-Finnish (FIN) AF: 0.000187 AC: 1 AN: 5359

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.000395 AC: 19 AN: 48048

Other (OTH) AF: 0.00 AC: 0 AN: 1441

Alfa AF: 0.000169 Hom.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

X-linked agammaglobulinemia Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.52
DANN	Benign	0.42
PhyloP100		-1.3
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: rs781937023; hg19: chrX-100604531; COSMIC: COSV58120585; COSMIC: COSV58120585;