rs700

chrX-101349769-T-G

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.*116A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 611,910 control chromosomes in the GnomAD database, including 40,549 homozygotes. There are 81,115 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (6184 hom., 11436 hem., cov: 22)
  • Exomes 𝑓: 0.44 (34365 hom. 69679 hem.)
• Consequence: BTK NM_000061.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0110

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=-0.92).
• BP6: Variant X-101349769-T-G is Benign according to our data. Variant chrX-101349769-T-G is described in ClinVar as [Benign]. Clinvar id is 367694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.488 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTK	NM_000061.3	c.*116A>C		3_prime_UTR_variant	19/19	ENST00000308731.8
BTK	NM_001287344.2	c.*116A>C		3_prime_UTR_variant	19/19
BTK	NM_001287345.2	c.*116A>C		3_prime_UTR_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTK	ENST00000308731.8	c.*116A>C		3_prime_UTR_variant	19/19	1	NM_000061.3	P3

Frequencies

GnomAD3 genomes AF: 0.357 AC: 39382 AN: 110247 Hom.: 6191 Cov.: 22 AF XY: 0.352 AC XY: 11435 AN XY: 32499

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.502

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.493

Gnomad OTH AF: 0.396

GnomAD4 exome AF: 0.435 AC: 218336 AN: 501610 Hom.: 34365 Cov.: 8 AF XY: 0.446 AC XY: 69679 AN XY: 156264

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.202

Gnomad4 ASJ exome AF: 0.544

Gnomad4 EAS exome AF: 0.188

Gnomad4 SAS exome AF: 0.340

Gnomad4 FIN exome AF: 0.511

Gnomad4 NFE exome AF: 0.486

Gnomad4 OTH exome AF: 0.431

GnomAD4 genome AF: 0.357 AC: 39360 AN: 110300 Hom.: 6184 Cov.: 22 AF XY: 0.351 AC XY: 11436 AN XY: 32562

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.285

Gnomad4 ASJ AF: 0.534

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.309

Gnomad4 FIN AF: 0.502

Gnomad4 NFE AF: 0.493

Gnomad4 OTH AF: 0.392

Alfa AF: 0.450 Hom.: 12146

Bravo AF: 0.331

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

X-linked agammaglobulinemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	1.7
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs700; hg19: chrX-100604757; COSMIC: COSV58118204; COSMIC: COSV58118204;