rs128620186

chrX-101375283-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate 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 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000061.3 (BTK) was described as [Pathogenic] in ClinVar as 863382
• 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/exons	MANE	UniProt
BTK	NM_000061.3	c.2T>C	p.Met1?	start_lost	2/19	ENST00000308731.8
BTK	NM_001287345.2	c.2T>C	p.Met1?	start_lost	3/17
BTK	NM_001287344.2	c.104T>C	p.Met35Thr	missense_variant	2/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTK	ENST00000308731.8	c.2T>C	p.Met1?	start_lost	2/19	1	NM_000061.3	P3

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2022

This variant is not present in population databases (gnomAD no frequency). 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 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

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1996

- -

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
MutationTaster	Benign	1.0	A;A
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;