NM_000061.3:c.-31+1832C>G

Variant names:

• chrX-101384230-G-C
• rs2239460
• NM_000061.3:c.-31+1832C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000061.3(BTK):​c.-31+1832C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0781 in 111,774 control chromosomes in the GnomAD database, including 296 homozygotes. There are 2,497 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.078 (296 hom., 2497 hem., cov: 23)
• Consequence: BTK NM_000061.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.227
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.-31+1832C>G		intron_variant	Intron 1 of 18	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.72+6248C>G		intron_variant	Intron 1 of 18		NP_001274273.1
BTK	NM_001287345.2	c.-196+1832C>G		intron_variant	Intron 1 of 16		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.-31+1832C>G		intron_variant	Intron 1 of 18	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes AF: 0.0782 AC: 8734 AN: 111720 Hom.: 295 Cov.: 23

Gnomad AFR AF: 0.0842

Gnomad AMI AF: 0.0206

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.0797

Gnomad EAS AF: 0.0365

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0223

Gnomad MID AF: 0.0879

Gnomad NFE AF: 0.0776

Gnomad OTH AF: 0.0837

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0781 AC: 8735 AN: 111774 Hom.: 296 Cov.: 23 AF XY: 0.0735 AC XY: 2497 AN XY: 33990

African (AFR) AF: 0.0842 AC: 2588 AN: 30751

American (AMR) AF: 0.0999 AC: 1048 AN: 10493

Ashkenazi Jewish (ASJ) AF: 0.0797 AC: 211 AN: 2648

East Asian (EAS) AF: 0.0366 AC: 131 AN: 3575

South Asian (SAS) AF: 0.126 AC: 339 AN: 2694

European-Finnish (FIN) AF: 0.0223 AC: 135 AN: 6054

Middle Eastern (MID) AF: 0.0917 AC: 20 AN: 218

European-Non Finnish (NFE) AF: 0.0776 AC: 4124 AN: 53134

Other (OTH) AF: 0.0819 AC: 125 AN: 1526

Alfa AF: 0.0180 Hom.: 87

Bravo AF: 0.0837

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.75
DANN	Benign	0.66
PhyloP100		-0.23
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: rs2239460; hg19: chrX-100639218;