X-101349693-C-T

Variant names:

• chrX-101349693-C-T
• rs1057403
• NM_000061.3:c.*192G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000061.3(BTK):​c.*192G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 442,227 control chromosomes in the GnomAD database, including 14,552 homozygotes. There are 35,609 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 0.32 (5892 hom., 10233 hem., cov: 22)
  • Exomes 𝑓: 0.24 (8660 hom. 25376 hem.)
• Consequence: BTK NM_000061.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.493
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.*192G>A		3_prime_UTR_variant	Exon 19 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.*192G>A		3_prime_UTR_variant	Exon 19 of 19		NP_001274273.1
BTK	NM_001287345.2	c.*192G>A		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.*192G>A		3_prime_UTR_variant	Exon 19 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes AF: 0.320 AC: 35251 AN: 110320 Hom.: 5884 Cov.: 22

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.0973

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.181

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.281

GnomAD4 exome AF: 0.237 AC: 78600 AN: 331854 Hom.: 8660 Cov.: 4 AF XY: 0.245 AC XY: 25376 AN XY: 103512

African (AFR) AF: 0.630 AC: 6629 AN: 10515

American (AMR) AF: 0.462 AC: 8245 AN: 17830

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 1411 AN: 9684

East Asian (EAS) AF: 0.473 AC: 12047 AN: 25455

South Asian (SAS) AF: 0.460 AC: 9643 AN: 20954

European-Finnish (FIN) AF: 0.155 AC: 4427 AN: 28504

Middle Eastern (MID) AF: 0.179 AC: 342 AN: 1915

European-Non Finnish (NFE) AF: 0.158 AC: 31132 AN: 197450

Other (OTH) AF: 0.242 AC: 4724 AN: 19547

GnomAD4 genome AF: 0.320 AC: 35298 AN: 110373 Hom.: 5892 Cov.: 22 AF XY: 0.313 AC XY: 10233 AN XY: 32671

African (AFR) AF: 0.629 AC: 18953 AN: 30133

American (AMR) AF: 0.349 AC: 3590 AN: 10275

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 400 AN: 2646

East Asian (EAS) AF: 0.439 AC: 1525 AN: 3475

South Asian (SAS) AF: 0.444 AC: 1153 AN: 2596

European-Finnish (FIN) AF: 0.154 AC: 900 AN: 5853

Middle Eastern (MID) AF: 0.190 AC: 41 AN: 216

European-Non Finnish (NFE) AF: 0.156 AC: 8242 AN: 52999

Other (OTH) AF: 0.285 AC: 428 AN: 1502

Alfa AF: 0.240 Hom.: 20845

Bravo AF: 0.355

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

X-linked agammaglobulinemia Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.0
DANN	Benign	0.82
PhyloP100		0.49
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: rs1057403; hg19: chrX-100604681; COSMIC: COSV58119536; COSMIC: COSV58119536;