chrX-101349551-A-C

Variant names:

• chrX-101349551-A-C
• rs183674618
• NM_000061.3:c.*334T>G

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.*334T>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 0.0139 in 229,791 control chromosomes in the GnomAD database, including 113 homozygotes. There are 668 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (100 hom., 605 hem., cov: 22)
  • Exomes 𝑓: 0.0039 (13 hom. 63 hem.)
• Consequence: BTK NM_000061.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.347
• Publications: 1 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=-0.85).
• BP6: Variant X-101349551-A-C is Benign according to our data. Variant chrX-101349551-A-C is described in ClinVar as [Benign]. Clinvar id is 367692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0842 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.*334T>G		3_prime_UTR_variant	Exon 19 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.*334T>G		3_prime_UTR_variant	Exon 19 of 19		NP_001274273.1
BTK	NM_001287345.2	c.*334T>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.*334T>G		3_prime_UTR_variant	Exon 19 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 2717 AN: 108243 Hom.: 99 Cov.: 22

Gnomad AFR AF: 0.0869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00117

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0338

Gnomad NFE AF: 0.000346

Gnomad OTH AF: 0.0111

GnomAD4 exome AF: 0.00385 AC: 468 AN: 121500 Hom.: 13 Cov.: 0 AF XY: 0.00213 AC XY: 63 AN XY: 29584

African (AFR) AF: 0.0677 AC: 335 AN: 4946

American (AMR) AF: 0.00664 AC: 35 AN: 5273

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4971

East Asian (EAS) AF: 0.00 AC: 0 AN: 12155

South Asian (SAS) AF: 0.00 AC: 0 AN: 3672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4098

Middle Eastern (MID) AF: 0.00721 AC: 4 AN: 555

European-Non Finnish (NFE) AF: 0.000220 AC: 17 AN: 77101

Other (OTH) AF: 0.00882 AC: 77 AN: 8729

GnomAD4 genome AF: 0.0252 AC: 2724 AN: 108291 Hom.: 100 Cov.: 22 AF XY: 0.0194 AC XY: 605 AN XY: 31231

African (AFR) AF: 0.0870 AC: 2572 AN: 29574

American (AMR) AF: 0.0106 AC: 107 AN: 10075

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2609

East Asian (EAS) AF: 0.00 AC: 0 AN: 3502

South Asian (SAS) AF: 0.00117 AC: 3 AN: 2554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5602

Middle Eastern (MID) AF: 0.0370 AC: 8 AN: 216

European-Non Finnish (NFE) AF: 0.000346 AC: 18 AN: 52037

Other (OTH) AF: 0.0110 AC: 16 AN: 1460

Alfa AF: 0.0227 Hom.: 75

Bravo AF: 0.0316

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	-0.85
CADD	Benign	3.4
DANN	Benign	0.56
PhyloP100		0.35
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: rs183674618; hg19: chrX-100604539;