rs128620189

Positions:

• chrX-101375188-T-A
• chrX-101375188-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000061.3(BTK):​c.97A>T​(p.Thr33Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.63

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• 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, 0.772

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTK	NM_000061.3	c.97A>T	p.Thr33Ser	missense_variant	2/19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.199A>T	p.Thr67Ser	missense_variant	2/19		NP_001274273.1
BTK	NM_001287345.2	c.97A>T	p.Thr33Ser	missense_variant	3/17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.97A>T	p.Thr33Ser	missense_variant	2/19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;.;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;T;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.6	.;.;.;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	.;D;.;D
REVEL	Uncertain	0.53
Sift	Benign	0.034	.;D;.;D
Sift4G	Benign	0.072	T;D;T;T
Polyphen		0.79, 0.47	.;P;.;P
Vest4		0.53
MutPred		0.53		Gain of phosphorylation at S38 (P = 0.1193);Gain of phosphorylation at S38 (P = 0.1193);.;Gain of phosphorylation at S38 (P = 0.1193);
MVP		0.93
MPC		1.3
ClinPred		0.96	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.92

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-100630176;