X-101375188-T-G

Variant names:

• chrX-101375188-T-G
• rs128620189
• NM_000061.3:c.97A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_000061.3(BTK):​c.97A>C​(p.Thr33Pro) 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: 23)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the BTK gene, where missense mutations are typically associated with disease (based on misZ statistic). 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). GenCC associations: The gene is linked to 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, 0.936
• PP5: Variant X-101375188-T-G is Pathogenic according to our data. Variant chrX-101375188-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 11351.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-101375188-T-G is described in Lovd as [Pathogenic]. Variant chrX-101375188-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.97A>C	p.Thr33Pro	missense_variant	Exon 2 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.199A>C	p.Thr67Pro	missense_variant	Exon 2 of 19		NP_001274273.1
BTK	NM_001287345.2	c.97A>C	p.Thr33Pro	missense_variant	Exon 3 of 17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.97A>C	p.Thr33Pro	missense_variant	Exon 2 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked agammaglobulinemia Pathogenic:1

Oct 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;.;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.4	.;.;.;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.6	.;D;.;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0070	.;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.90, 1.0	.;P;.;D
Vest4		0.79
MutPred		0.76		Loss of phosphorylation at T33 (P = 0.0513);Loss of phosphorylation at T33 (P = 0.0513);.;Loss of phosphorylation at T33 (P = 0.0513);
MVP		0.99
MPC		2.8
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs128620189; hg19: chrX-100630176;