rs1135363

Variant names:

• chrX-101353203-G-A
• rs1135363
• NM_000061.3:c.1899C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-101353203-G-A
• chrX-101353203-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000061.3(BTK):​c.1899C>T​(p.Cys633Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,206,338 control chromosomes in the GnomAD database, including 32,609 homozygotes. There are 88,939 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (8809 hom., 11848 hem., cov: 22)
  • Exomes 𝑓: 0.21 (23800 hom. 77091 hem.)
• Consequence: BTK NM_000061.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.50
• Publications: 18 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 -16 ACMG points.

• BP6: Variant X-101353203-G-A is Benign according to our data. Variant chrX-101353203-G-A is described in ClinVar as Benign. ClinVar VariationId is 254784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

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.1899C>T	p.Cys633Cys	synonymous	Exon 18 of 19	NP_000052.1	Q06187-1
	BTK	NM_001287344.2		c.2001C>T	p.Cys667Cys	synonymous	Exon 18 of 19	NP_001274273.1	Q06187-2
	BTK	NM_001287345.2		c.1371C>T	p.Cys457Cys	synonymous	Exon 16 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.1899C>T	p.Cys633Cys	synonymous	Exon 18 of 19	ENSP00000308176.8	Q06187-1
	BTK	ENST00000621635.4	TSL:1	c.2001C>T	p.Cys667Cys	synonymous	Exon 18 of 19	ENSP00000483570.1	Q06187-2
	BTK	ENST00000695631.1		c.158C>T	p.Ala53Val	missense	Exon 2 of 3	ENSP00000512070.1	A0A8Q3SI38

Frequencies

GnomAD3 genomes AF: 0.373 AC: 41024 AN: 110014 Hom.: 8803 Cov.: 22

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.319

GnomAD2 exomes AF: 0.314 AC: 57197 AN: 182369 AF XY: 0.288

Gnomad AFR exome AF: 0.821

Gnomad AMR exome AF: 0.518

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.446

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.243

GnomAD4 exome AF: 0.210 AC: 230566 AN: 1096272 Hom.: 23800 Cov.: 31 AF XY: 0.213 AC XY: 77091 AN XY: 362110

African (AFR) AF: 0.828 AC: 21836 AN: 26359

American (AMR) AF: 0.501 AC: 17617 AN: 35144

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 3044 AN: 19364

East Asian (EAS) AF: 0.469 AC: 14148 AN: 30189

South Asian (SAS) AF: 0.435 AC: 23440 AN: 53918

European-Finnish (FIN) AF: 0.158 AC: 6403 AN: 40518

Middle Eastern (MID) AF: 0.192 AC: 791 AN: 4110

European-Non Finnish (NFE) AF: 0.157 AC: 131846 AN: 840647

Other (OTH) AF: 0.249 AC: 11441 AN: 46023

GnomAD4 genome AF: 0.373 AC: 41088 AN: 110066 Hom.: 8809 Cov.: 22 AF XY: 0.366 AC XY: 11848 AN XY: 32336

African (AFR) AF: 0.808 AC: 24344 AN: 30128

American (AMR) AF: 0.374 AC: 3834 AN: 10248

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 414 AN: 2631

East Asian (EAS) AF: 0.440 AC: 1537 AN: 3496

South Asian (SAS) AF: 0.448 AC: 1160 AN: 2592

European-Finnish (FIN) AF: 0.157 AC: 905 AN: 5770

Middle Eastern (MID) AF: 0.207 AC: 45 AN: 217

European-Non Finnish (NFE) AF: 0.157 AC: 8301 AN: 52818

Other (OTH) AF: 0.323 AC: 481 AN: 1487

Alfa AF: 0.221 Hom.: 8305

Bravo AF: 0.415

EpiCase AF: 0.161

EpiControl AF: 0.151

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	X-linked agammaglobulinemia with growth hormone deficiency (3)
-	-	2	not provided (2)
-	-	2	X-linked agammaglobulinemia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.64
PhyloP100		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1135363; hg19: chrX-100608191; COSMIC: COSV58117908; COSMIC: COSV58117908;