rs1057403

Variant names:

• chrX-101349693-C-T
• rs1057403
• NM_000061.3:c.*192G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-101349693-C-T
• chrX-101349693-C-A
• chrX-101349693-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000061.3(BTK):​c.*192G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 442,227 control chromosomes in the GnomAD database, including 14,552 homozygotes. There are 35,609 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (5892 hom., 10233 hem., cov: 22)
  • Exomes 𝑓: 0.24 (8660 hom. 25376 hem.)
• Consequence: BTK NM_000061.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.493
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-101349693-C-T is Benign according to our data. Variant chrX-101349693-C-T is described in ClinVar as Benign. ClinVar VariationId is 367693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.621 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.*192G>A		3_prime_UTR	Exon 19 of 19	NP_000052.1	Q06187-1
	BTK	NM_001287344.2		c.*192G>A		3_prime_UTR	Exon 19 of 19	NP_001274273.1	Q06187-2
	BTK	NM_001287345.2		c.*192G>A		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.*192G>A		3_prime_UTR	Exon 19 of 19	ENSP00000308176.8	Q06187-1
	BTK	ENST00000621635.4	TSL:1	c.*192G>A		3_prime_UTR	Exon 19 of 19	ENSP00000483570.1	Q06187-2
	BTK	ENST00000944957.1		c.*192G>A		3_prime_UTR	Exon 19 of 19	ENSP00000615016.1

Frequencies

GnomAD3 genomes AF: 0.320 AC: 35251 AN: 110320 Hom.: 5884 Cov.: 22

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.0973

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.181

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.281

GnomAD4 exome AF: 0.237 AC: 78600 AN: 331854 Hom.: 8660 Cov.: 4 AF XY: 0.245 AC XY: 25376 AN XY: 103512

African (AFR) AF: 0.630 AC: 6629 AN: 10515

American (AMR) AF: 0.462 AC: 8245 AN: 17830

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 1411 AN: 9684

East Asian (EAS) AF: 0.473 AC: 12047 AN: 25455

South Asian (SAS) AF: 0.460 AC: 9643 AN: 20954

European-Finnish (FIN) AF: 0.155 AC: 4427 AN: 28504

Middle Eastern (MID) AF: 0.179 AC: 342 AN: 1915

European-Non Finnish (NFE) AF: 0.158 AC: 31132 AN: 197450

Other (OTH) AF: 0.242 AC: 4724 AN: 19547

GnomAD4 genome AF: 0.320 AC: 35298 AN: 110373 Hom.: 5892 Cov.: 22 AF XY: 0.313 AC XY: 10233 AN XY: 32671

African (AFR) AF: 0.629 AC: 18953 AN: 30133

American (AMR) AF: 0.349 AC: 3590 AN: 10275

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 400 AN: 2646

East Asian (EAS) AF: 0.439 AC: 1525 AN: 3475

South Asian (SAS) AF: 0.444 AC: 1153 AN: 2596

European-Finnish (FIN) AF: 0.154 AC: 900 AN: 5853

Middle Eastern (MID) AF: 0.190 AC: 41 AN: 216

European-Non Finnish (NFE) AF: 0.156 AC: 8242 AN: 52999

Other (OTH) AF: 0.285 AC: 428 AN: 1502

Alfa AF: 0.240 Hom.: 20845

Bravo AF: 0.355

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	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	-0.60
CADD	Benign	7.0
DANN	Benign	0.82
PhyloP100		0.49
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: rs1057403; hg19: chrX-100604681; COSMIC: COSV58119536; COSMIC: COSV58119536;