rs782702231

Variant names:

• chrX-101349965-A-G
• rs782702231
• NM_000061.3:c.1909-9T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000061.3(BTK):​c.1909-9T>C variant causes a intron change. The variant allele was found at a frequency of 0.000655 in 1,180,184 control chromosomes in the GnomAD database, including 1 homozygotes. There are 226 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., 8 hem., cov: 22)
  • Exomes 𝑓: 0.00069 (1 hom. 218 hem.)
• Consequence: BTK NM_000061.3 intron
• Scores: Splicing: ADA: 0.02493
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 6.27
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-101349965-A-G is Benign according to our data. Variant chrX-101349965-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194911.
• 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.1909-9T>C		intron	N/A	NP_000052.1	Q06187-1
	BTK	NM_001287344.2		c.2011-9T>C		intron	N/A	NP_001274273.1	Q06187-2
	BTK	NM_001287345.2		c.1381-9T>C		intron	N/A	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.1909-9T>C		intron	N/A	ENSP00000308176.8	Q06187-1
	BTK	ENST00000621635.4	TSL:1	c.2011-9T>C		intron	N/A	ENSP00000483570.1	Q06187-2
	BTK	ENST00000944957.1		c.1990-9T>C		intron	N/A	ENSP00000615016.1

Frequencies

GnomAD3 genomes AF: 0.000279 AC: 31 AN: 111143 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000338

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000452

Gnomad OTH AF: 0.000670

GnomAD2 exomes AF: 0.000295 AC: 54 AN: 182780 AF XY: 0.000341

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000314

Gnomad NFE exome AF: 0.000492

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000694 AC: 742 AN: 1068987 Hom.: 1 Cov.: 27 AF XY: 0.000648 AC XY: 218 AN XY: 336445

African (AFR) AF: 0.000116 AC: 3 AN: 25901

American (AMR) AF: 0.00 AC: 0 AN: 35175

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19207

East Asian (EAS) AF: 0.00 AC: 0 AN: 30102

South Asian (SAS) AF: 0.000112 AC: 6 AN: 53437

European-Finnish (FIN) AF: 0.000568 AC: 23 AN: 40479

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4074

European-Non Finnish (NFE) AF: 0.000845 AC: 689 AN: 815454

Other (OTH) AF: 0.000443 AC: 20 AN: 45158

GnomAD4 genome AF: 0.000279 AC: 31 AN: 111197 Hom.: 0 Cov.: 22 AF XY: 0.000240 AC XY: 8 AN XY: 33365

African (AFR) AF: 0.000131 AC: 4 AN: 30550

American (AMR) AF: 0.00 AC: 0 AN: 10361

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2636

East Asian (EAS) AF: 0.00 AC: 0 AN: 3577

South Asian (SAS) AF: 0.00 AC: 0 AN: 2665

European-Finnish (FIN) AF: 0.000338 AC: 2 AN: 5923

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000452 AC: 24 AN: 53069

Other (OTH) AF: 0.000661 AC: 1 AN: 1512

Alfa AF: 0.000364 Hom.: 3

Bravo AF: 0.000200

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	X-linked agammaglobulinemia with growth hormone deficiency (2)
-	-	1	not specified (1)
-	-	1	X-linked agammaglobulinemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	20
DANN	Benign	0.82
PhyloP100		6.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.025
dbscSNV1_RF	Benign	0.20
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

Other links and lift over

dbSNP: rs782702231; hg19: chrX-100604953;