rs1122765

Variant names:

• chrX-101349664-C-A
• rs1122765
• NM_000061.3:c.*221G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000061.3(BTK):​c.*221G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 421,263 control chromosomes in the GnomAD database, including 6 homozygotes. There are 120 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0032 (4 hom., 91 hem., cov: 22)
  • Exomes 𝑓: 0.00043 (2 hom. 29 hem.)
• Consequence: BTK NM_000061.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.190
• 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: 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-101349664-C-A is Benign according to our data. Variant chrX-101349664-C-A is described in ClinVar as Benign. ClinVar VariationId is 912392.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 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.*221G>T		3_prime_UTR	Exon 19 of 19	NP_000052.1	Q06187-1
	BTK	NM_001287344.2		c.*221G>T		3_prime_UTR	Exon 19 of 19	NP_001274273.1	Q06187-2
	BTK	NM_001287345.2		c.*221G>T		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.*221G>T		3_prime_UTR	Exon 19 of 19	ENSP00000308176.8	Q06187-1
	BTK	ENST00000621635.4	TSL:1	c.*221G>T		3_prime_UTR	Exon 19 of 19	ENSP00000483570.1	Q06187-2
	BTK	ENST00000944957.1		c.*221G>T		3_prime_UTR	Exon 19 of 19	ENSP00000615016.1

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 352 AN: 111336 Hom.: 4 Cov.: 22

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000578

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000378

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000670

GnomAD4 exome AF: 0.000426 AC: 132 AN: 309873 Hom.: 2 Cov.: 3 AF XY: 0.000302 AC XY: 29 AN XY: 95871

African (AFR) AF: 0.0119 AC: 117 AN: 9802

American (AMR) AF: 0.000702 AC: 10 AN: 14250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9405

East Asian (EAS) AF: 0.00 AC: 0 AN: 23756

South Asian (SAS) AF: 0.00 AC: 0 AN: 20793

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23495

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1486

European-Non Finnish (NFE) AF: 0.00000532 AC: 1 AN: 188044

Other (OTH) AF: 0.000212 AC: 4 AN: 18842

GnomAD4 genome AF: 0.00316 AC: 352 AN: 111390 Hom.: 4 Cov.: 22 AF XY: 0.00271 AC XY: 91 AN XY: 33592

African (AFR) AF: 0.0112 AC: 344 AN: 30618

American (AMR) AF: 0.000578 AC: 6 AN: 10389

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3565

South Asian (SAS) AF: 0.000380 AC: 1 AN: 2635

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5956

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53163

Other (OTH) AF: 0.000662 AC: 1 AN: 1511

Alfa AF: 0.00167 Hom.: 48

Bravo AF: 0.00359

ClinVar

ClinVar submissions

Significance: Benign

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	-0.86
CADD	Benign	1.4
DANN	Benign	0.74
PhyloP100		-0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs1122765; hg19: chrX-100604652;