rs128620186

Variant names:

• chrX-101375283-A-G
• rs128620186
• NM_000061.3:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000061.3(BTK):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: BTK NM_000061.3 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.72
• Publications: 2 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 34 pathogenic variants. Next in-frame start position is after 89 codons. Genomic position: 101371677. Lost 0.134 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-101375283-A-G is Pathogenic according to our data. Variant chrX-101375283-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2T>C	p.Met1?	start_lost	Exon 2 of 19	NP_000052.1
	BTK	NM_001287345.2		c.2T>C	p.Met1?	start_lost	Exon 3 of 17	NP_001274274.1
	BTK	NM_001287344.2		c.104T>C	p.Met35Thr	missense	Exon 2 of 19	NP_001274273.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTK	ENST00000308731.8	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 2 of 19	ENSP00000308176.8
	BTK	ENST00000621635.4	TSL:1	c.104T>C	p.Met35Thr	missense	Exon 2 of 19	ENSP00000483570.1
	BTK	ENST00000695614.1		c.2T>C	p.Met1?	start_lost	Exon 2 of 19	ENSP00000512053.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

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
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.53
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.49	D
PhyloP100		7.7
PROVEAN	Benign	-0.17	N
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.46	P
Vest4		0.94
MutPred		0.63		Gain of catalytic residue at M1 (P = 0.007)
MVP		1.0
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.88
gMVP		0.96
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs128620186; hg19: chrX-100630271;