rs138411530

Variant names:

• chrX-101375133-G-A
• rs138411530
• NM_000061.3:c.141+11C>T

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.141+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00773 in 1,209,389 control chromosomes in the GnomAD database, including 29 homozygotes. There are 2,872 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 0.0061 (1 hom., 175 hem., cov: 23)
  • Exomes 𝑓: 0.0079 (28 hom. 2697 hem.)
• Consequence: BTK NM_000061.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -0.328
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-101375133-G-A is Benign according to our data. Variant chrX-101375133-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235712.
• BS2: High Hemizygotes in GnomAd4 at 175 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.141+11C>T		intron	N/A	NP_000052.1	Q06187-1
	BTK	NM_001287344.2		c.243+11C>T		intron	N/A	NP_001274273.1	Q06187-2
	BTK	NM_001287345.2		c.141+11C>T		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.141+11C>T		intron	N/A	ENSP00000308176.8	Q06187-1
	BTK	ENST00000621635.4	TSL:1	c.243+11C>T		intron	N/A	ENSP00000483570.1	Q06187-2
	BTK	ENST00000944957.1		c.141+11C>T		intron	N/A	ENSP00000615016.1

Frequencies

GnomAD3 genomes AF: 0.00605 AC: 677 AN: 111813 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.000975

Gnomad AMI AF: 0.00146

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00532

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00885

Gnomad OTH AF: 0.00597

GnomAD2 exomes AF: 0.00482 AC: 882 AN: 183166 AF XY: 0.00477

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00576

Gnomad NFE exome AF: 0.00813

Gnomad OTH exome AF: 0.00553

GnomAD4 exome AF: 0.00790 AC: 8667 AN: 1097523 Hom.: 28 Cov.: 30 AF XY: 0.00743 AC XY: 2697 AN XY: 362901

African (AFR) AF: 0.000947 AC: 25 AN: 26395

American (AMR) AF: 0.00347 AC: 122 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.000155 AC: 3 AN: 19372

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30202

South Asian (SAS) AF: 0.0000739 AC: 4 AN: 54129

European-Finnish (FIN) AF: 0.00652 AC: 264 AN: 40502

Middle Eastern (MID) AF: 0.000726 AC: 3 AN: 4134

European-Non Finnish (NFE) AF: 0.00946 AC: 7962 AN: 841516

Other (OTH) AF: 0.00614 AC: 283 AN: 46069

GnomAD4 genome AF: 0.00605 AC: 677 AN: 111866 Hom.: 1 Cov.: 23 AF XY: 0.00514 AC XY: 175 AN XY: 34056

African (AFR) AF: 0.000973 AC: 30 AN: 30827

American (AMR) AF: 0.0128 AC: 134 AN: 10480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3578

South Asian (SAS) AF: 0.00 AC: 0 AN: 2688

European-Finnish (FIN) AF: 0.00532 AC: 32 AN: 6019

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

European-Non Finnish (NFE) AF: 0.00885 AC: 471 AN: 53194

Other (OTH) AF: 0.00590 AC: 9 AN: 1526

Alfa AF: 0.00716 Hom.: 238

Bravo AF: 0.00666

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	2	X-linked agammaglobulinemia (2)
-	-	2	X-linked agammaglobulinemia with growth hormone deficiency (2)
-	1	-	X-linked agammaglobulinemia;C0472813:X-linked agammaglobulinemia with growth hormone deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.1
DANN	Benign	0.73
PhyloP100		-0.33
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: rs138411530; hg19: chrX-100630121;