NM_000061.3:c.*192G>A

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_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. Variant has been reported in ClinVar as Benign (★★).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-101349693-C-T is Benign according to our data. Variant chrX-101349693-C-T is described in ClinVar as [Benign]. Clinvar id is 367693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	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 AF XY: 0.313 AC XY: 10199 AN XY: 32608

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

Gnomad4 AFR exome AF: 0.630

Gnomad4 AMR exome AF: 0.462

Gnomad4 ASJ exome AF: 0.146

Gnomad4 EAS exome AF: 0.473

Gnomad4 SAS exome AF: 0.460

Gnomad4 FIN exome AF: 0.155

Gnomad4 NFE exome AF: 0.158

Gnomad4 OTH exome AF: 0.242

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

Gnomad4 AFR AF: 0.629

Gnomad4 AMR AF: 0.349

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.439

Gnomad4 SAS AF: 0.444

Gnomad4 FIN AF: 0.154

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.285

Alfa AF: 0.185 Hom.: 9957

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057403; hg19: chrX-100604681; COSMIC: COSV58119536; COSMIC: COSV58119536;