X-101349543-A-C

Variant names:

• chrX-101349543-A-C
• rs781937023
• NM_000061.3:c.*342T>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000061.3(BTK):​c.*342T>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 0.000256 in 207,045 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., 8 hem., cov: 21)
  • Exomes 𝑓: 0.00021 (0 hom. 4 hem.)
• Consequence: BTK NM_000061.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.33
• Publications: 0 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: Labcorp Genetics (formerly Invitae), ClinGen
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000061.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTK	NM_000061.3	MANE Select	c.*342T>G		3_prime_UTR	Exon 19 of 19	NP_000052.1	Q06187-1
	BTK	NM_001287344.2		c.*342T>G		3_prime_UTR	Exon 19 of 19	NP_001274273.1	Q06187-2
	BTK	NM_001287345.2		c.*342T>G		3_prime_UTR	Exon 17 of 17	NP_001274274.1	Q5JY90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTK	ENST00000308731.8	TSL:1 MANE Select	c.*342T>G		3_prime_UTR	Exon 19 of 19	ENSP00000308176.8	Q06187-1
	BTK	ENST00000621635.4	TSL:1	c.*342T>G		3_prime_UTR	Exon 19 of 19	ENSP00000483570.1	Q06187-2
	BTK	ENST00000944957.1		c.*342T>G		3_prime_UTR	Exon 19 of 19	ENSP00000615016.1

Frequencies

GnomAD3 genomes AF: 0.000298 AC: 31 AN: 103986 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000671

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000711

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000566

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000187

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000395

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000214 AC: 22 AN: 103007 Hom.: 0 Cov.: 0 AF XY: 0.000154 AC XY: 4 AN XY: 26047

African (AFR) AF: 0.000443 AC: 2 AN: 4519

American (AMR) AF: 0.00 AC: 0 AN: 4753

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4413

East Asian (EAS) AF: 0.00 AC: 0 AN: 11304

South Asian (SAS) AF: 0.00 AC: 0 AN: 3265

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 512

European-Non Finnish (NFE) AF: 0.000299 AC: 19 AN: 63594

Other (OTH) AF: 0.000133 AC: 1 AN: 7519

GnomAD4 genome AF: 0.000298 AC: 31 AN: 104038 Hom.: 0 Cov.: 21 AF XY: 0.000253 AC XY: 8 AN XY: 31630

African (AFR) AF: 0.0000669 AC: 2 AN: 29897

American (AMR) AF: 0.000710 AC: 7 AN: 9864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2546

East Asian (EAS) AF: 0.000567 AC: 2 AN: 3525

South Asian (SAS) AF: 0.00 AC: 0 AN: 2609

European-Finnish (FIN) AF: 0.000187 AC: 1 AN: 5359

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.000395 AC: 19 AN: 48048

Other (OTH) AF: 0.00 AC: 0 AN: 1441

Alfa AF: 0.000169 Hom.: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	X-linked agammaglobulinemia (1)
-	1	-	X-linked agammaglobulinemia with growth hormone deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.52
DANN	Benign	0.42
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

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: rs781937023; hg19: chrX-100604531; COSMIC: COSV58120585; COSMIC: COSV58120585;