rs193922125

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate

The ENST00000308731.8(BTK):​c.1511A>T​(p.Asp504Val) variant causes a missense 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
ENST00000308731.8 missense

Scores

15
1
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.02
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000308731.8
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, 0.988
PP5
Variant X-101356107-T-A is Pathogenic according to our data. Variant chrX-101356107-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35758.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-101356107-T-A is described in Lovd as [Pathogenic]. Variant chrX-101356107-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BTKNM_000061.3 linkuse as main transcriptc.1511A>T p.Asp504Val missense_variant 15/19 ENST00000308731.8 NP_000052.1
BTKNM_001287344.2 linkuse as main transcriptc.1613A>T p.Asp538Val missense_variant 15/19 NP_001274273.1
BTKNM_001287345.2 linkuse as main transcriptc.1039-1413A>T intron_variant NP_001274274.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BTKENST00000308731.8 linkuse as main transcriptc.1511A>T p.Asp504Val missense_variant 15/191 NM_000061.3 ENSP00000308176 P3Q06187-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

X-linked agammaglobulinemia Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testing;curationWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 18, 2011- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.64
CADD
Pathogenic
34
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.89
D;.;D
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.4
.;.;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-7.8
.;.;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
.;.;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
.;.;D
Vest4
0.98
MutPred
0.89
Gain of methylation at K503 (P = 0.0458);.;Gain of methylation at K503 (P = 0.0458);
MVP
1.0
MPC
3.1
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.99
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.64
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.64
Position offset: 2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs193922125; hg19: chrX-100611095; API