rs5991926

Positions:

• chrX-101358637-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000061.3(BTK):​c.954T>C​(p.Ser318Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,209,071 control chromosomes in the GnomAD database, including 93 homozygotes. There are 1,212 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (50 hom., 518 hem., cov: 22)
  • Exomes 𝑓: 0.0022 (43 hom. 694 hem.)
• Consequence: BTK NM_000061.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.20

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant X-101358637-A-G is Benign according to our data. Variant chrX-101358637-A-G is described in ClinVar as [Benign]. Clinvar id is 367695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101358637-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTK	NM_000061.3	c.954T>C	p.Ser318Ser	synonymous_variant	11/19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.1056T>C	p.Ser352Ser	synonymous_variant	11/19		NP_001274273.1
BTK	NM_001287345.2	c.954T>C	p.Ser318Ser	synonymous_variant	12/17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.954T>C	p.Ser318Ser	synonymous_variant	11/19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2024 AN: 111856 Hom.: 50 Cov.: 22 AF XY: 0.0151 AC XY: 514 AN XY: 34008

Gnomad AFR AF: 0.0612

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00815

Gnomad ASJ AF: 0.00416

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.000489

Gnomad OTH AF: 0.0132

GnomAD3 exomes AF: 0.00597 AC: 1096 AN: 183505 Hom.: 25 AF XY: 0.00386 AC XY: 262 AN XY: 67935

Gnomad AFR exome AF: 0.0681

Gnomad AMR exome AF: 0.00365

Gnomad ASJ exome AF: 0.00574

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000403

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00224 AC: 2456 AN: 1097162 Hom.: 43 Cov.: 30 AF XY: 0.00191 AC XY: 694 AN XY: 362550

Gnomad4 AFR exome AF: 0.0645

Gnomad4 AMR exome AF: 0.00446

Gnomad4 ASJ exome AF: 0.00506

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000222

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000199

Gnomad4 OTH exome AF: 0.00595

GnomAD4 genome AF: 0.0181 AC: 2025 AN: 111909 Hom.: 50 Cov.: 22 AF XY: 0.0152 AC XY: 518 AN XY: 34071

Gnomad4 AFR AF: 0.0611

Gnomad4 AMR AF: 0.00814

Gnomad4 ASJ AF: 0.00416

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000489

Gnomad4 OTH AF: 0.0131

Alfa AF: 0.0132 Hom.: 69

Bravo AF: 0.0226

EpiCase AF: 0.00104

EpiControl AF: 0.000771

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2019	- -

X-linked agammaglobulinemia Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	10
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5991926; hg19: chrX-100613625;