X-101349769-T-G

Variant names:

• chrX-101349769-T-G
• rs700
• NM_000061.3:c.*116A>C

Variant summary

Our verdict is Benign. The variant received -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:6
• Conservation: PhyloP100: 0.0110
• Publications: 17 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 -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 rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.*116A>C		3_prime_UTR_variant	Exon 19 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.*116A>C		3_prime_UTR_variant	Exon 19 of 19		NP_001274273.1
BTK	NM_001287345.2	c.*116A>C		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.*116A>C		3_prime_UTR_variant	Exon 19 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes AF: 0.357 AC: 39382 AN: 110247 Hom.: 6191 Cov.: 22

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

African (AFR) AF: 0.109 AC: 1502 AN: 13774

American (AMR) AF: 0.202 AC: 5314 AN: 26351

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 7446 AN: 13678

East Asian (EAS) AF: 0.188 AC: 5124 AN: 27191

South Asian (SAS) AF: 0.340 AC: 12136 AN: 35746

European-Finnish (FIN) AF: 0.511 AC: 19484 AN: 38096

Middle Eastern (MID) AF: 0.543 AC: 1597 AN: 2942

European-Non Finnish (NFE) AF: 0.486 AC: 154610 AN: 318042

Other (OTH) AF: 0.431 AC: 11123 AN: 25790

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

African (AFR) AF: 0.115 AC: 3515 AN: 30444

American (AMR) AF: 0.285 AC: 2936 AN: 10295

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1398 AN: 2619

East Asian (EAS) AF: 0.231 AC: 804 AN: 3488

South Asian (SAS) AF: 0.309 AC: 810 AN: 2622

European-Finnish (FIN) AF: 0.502 AC: 2879 AN: 5731

Middle Eastern (MID) AF: 0.514 AC: 111 AN: 216

European-Non Finnish (NFE) AF: 0.493 AC: 25975 AN: 52714

Other (OTH) AF: 0.392 AC: 589 AN: 1504

Alfa AF: 0.426 Hom.: 16460

Bravo AF: 0.331

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

X-linked agammaglobulinemia Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.92
CADD	Benign	1.7
DANN	Benign	0.55
PhyloP100		0.011
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs700; hg19: chrX-100604757; COSMIC: COSV58118204; COSMIC: COSV58118204;