X-101349910-A-G

Position:

• chrX-101349910-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_000061.3(BTK):​c.1955T>C​(p.Leu652Pro) variant causes a missense change. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.59

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a helix (size 13) in uniprot entity BTK_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000061.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BTK. . Gene score misZ 4.0394 (greater than the threshold 3.09). GenCC has associacion of gene with short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia, Bruton-type agammaglobulinemia, isolated growth hormone deficiency type III.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831
• PP5: Variant X-101349910-A-G is Pathogenic according to our data. Variant chrX-101349910-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 11392.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-101349910-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTK	NM_000061.3	c.1955T>C	p.Leu652Pro	missense_variant	19/19	ENST00000308731.8
BTK	NM_001287344.2	c.2057T>C	p.Leu686Pro	missense_variant	19/19
BTK	NM_001287345.2	c.1427T>C	p.Leu476Pro	missense_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTK	ENST00000308731.8	c.1955T>C	p.Leu652Pro	missense_variant	19/19	1	NM_000061.3	P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked agammaglobulinemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	.;.;D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	-0.0050	T
MutationAssessor	Benign	0.16	.;.;N
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.85	N;.;N
REVEL	Uncertain	0.55
Sift	Benign	0.12	T;.;T
Sift4G	Benign	0.27	T;T;T
Polyphen		1.0	D;.;P
Vest4		0.74
MutPred		0.66		.;.;Loss of stability (P = 0.0032);
MVP		0.99
MPC		2.4
ClinPred		0.63	D
GERP RS		5.1
Varity_R		0.87
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs128622212; hg19: chrX-100604898;