rs128620186

Variant names:

• chrX-101375283-A-G
• rs128620186
• NM_000061.3:c.2T>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000061.3(BTK):​c.2T>C​(p.Met1?) variant causes a start lost 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: BTK NM_000061.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.72

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 10 pathogenic variants. Next in-frame start position is after 89 codons. Genomic position: 101371677. Lost 0.134 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-101375283-A-G is Pathogenic according to our data. Variant chrX-101375283-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 11349.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-101375283-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.2T>C	p.Met1?	start_lost	Exon 2 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287345.2	c.2T>C	p.Met1?	start_lost	Exon 3 of 17		NP_001274274.1
BTK	NM_001287344.2	c.104T>C	p.Met35Thr	missense_variant	Exon 2 of 19		NP_001274273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.2T>C	p.Met1?	start_lost	Exon 2 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:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency Pathogenic:1

Dec 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 11349). Disruption of the initiator codon has been observed in individuals with clinical features of BTK-related conditions (PMID: 7849697, 8644706, 10737994, 23335184). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the BTK mRNA. The next in-frame methionine is located at codon 89. -

X-linked agammaglobulinemia Pathogenic:1

Mar 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.53
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;.;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;T;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.49	D
PROVEAN	Benign	-0.17	.;N;.;N
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	.;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.46, 0.97	.;P;.;D
Vest4		0.94
MutPred		0.63		Gain of catalytic residue at M1 (P = 0.007);Gain of catalytic residue at M1 (P = 0.007);.;Gain of catalytic residue at M1 (P = 0.007);
MVP		1.0
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.88
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs128620186; hg19: chrX-100630271;