X-101349693-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000061.3(BTK):​c.*192G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: BTK NM_000061.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).

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>C		3_prime_UTR	Exon 19 of 19	NP_000052.1	Q06187-1
	BTK	NM_001287344.2		c.*192G>C		3_prime_UTR	Exon 19 of 19	NP_001274273.1	Q06187-2
	BTK	NM_001287345.2		c.*192G>C		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>C		3_prime_UTR	Exon 19 of 19	ENSP00000308176.8	Q06187-1
	BTK	ENST00000621635.4	TSL:1	c.*192G>C		3_prime_UTR	Exon 19 of 19	ENSP00000483570.1	Q06187-2
	BTK	ENST00000944957.1		c.*192G>C		3_prime_UTR	Exon 19 of 19	ENSP00000615016.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 332180 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 103592

African (AFR) AF: 0.00 AC: 0 AN: 10522

American (AMR) AF: 0.00 AC: 0 AN: 17867

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9688

East Asian (EAS) AF: 0.00 AC: 0 AN: 25474

South Asian (SAS) AF: 0.00 AC: 0 AN: 20974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28541

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1915

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 197627

Other (OTH) AF: 0.00 AC: 0 AN: 19572

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.2
DANN	Benign	0.77
PhyloP100		0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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;