rs128621208

Variant names:

• chrX-101353282-G-T
• rs128621208
• NM_000061.3:c.1820C>A

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.1820C>A​(p.Ala607Asp) 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: 5.58

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 domain Protein kinase (size 253) in uniprot entity BTK_HUMAN there are 43 pathogenic changes around while only 1 benign (98%) in NM_000061.3
• 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, 0.83
• PP5: Variant X-101353282-G-T is Pathogenic according to our data. Variant chrX-101353282-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 11387.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-101353282-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.1820C>A	p.Ala607Asp	missense_variant	Exon 18 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.1922C>A	p.Ala641Asp	missense_variant	Exon 18 of 19		NP_001274273.1
BTK	NM_001287345.2	c.1292C>A	p.Ala431Asp	missense_variant	Exon 16 of 17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.1820C>A	p.Ala607Asp	missense_variant	Exon 18 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked agammaglobulinemia Pathogenic:1

Jan 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	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;.;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.7	.;.;L
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.1	D;.;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.29	B;.;P
Vest4		0.63
MutPred		0.53		.;.;Gain of disorder (P = 0.053);
MVP		1.0
MPC		2.1
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.98

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: rs128621208; hg19: chrX-100608270;