chrX-101358343-C-T

Variant names:

• chrX-101358343-C-T
• rs1555978130
• NM_000061.3:c.1069G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000061.3(BTK):​c.1069G>A​(p.Glu357Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17
• 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: ClinGen, Labcorp Genetics (formerly Invitae)
• short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000061.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 90 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 4.0394 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Bruton-type agammaglobulinemia, short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia, isolated growth hormone deficiency type III.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTK	NM_000061.3	MANE Select	c.1069G>A	p.Glu357Lys	missense	Exon 12 of 19	NP_000052.1
	BTK	NM_001287344.2		c.1171G>A	p.Glu391Lys	missense	Exon 12 of 19	NP_001274273.1
	BTK	NM_001287345.2		c.1038+31G>A		intron	N/A	NP_001274274.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTK	ENST00000308731.8	TSL:1 MANE Select	c.1069G>A	p.Glu357Lys	missense	Exon 12 of 19	ENSP00000308176.8
	BTK	ENST00000621635.4	TSL:1	c.1171G>A	p.Glu391Lys	missense	Exon 12 of 19	ENSP00000483570.1
	BTK	ENST00000695614.1		c.1069G>A	p.Glu357Lys	missense	Exon 12 of 19	ENSP00000512053.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	X-linked agammaglobulinemia with growth hormone deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.2
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.76
Sift	Benign	0.30	T
Sift4G	Benign	0.30	T
Polyphen		0.99	D
Vest4		0.52
MutPred		0.66		Gain of methylation at E357 (P = 0.0252)
MVP		0.99
MPC		2.6
ClinPred		0.93	D
GERP RS		5.9
Varity_R		0.78
gMVP		0.97
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555978130; hg19: chrX-100613331; COSMIC: COSV100437985; COSMIC: COSV100437985;