chrX-101356177-A-T

Variant names:

• chrX-101356177-A-T
• rs1057519826
• NM_000061.3:c.1441T>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PP2 PP3_Moderate PP5

The NM_000061.3(BTK):​c.1441T>A​(p.Cys481Ser) 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.31

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 10 ACMG points.

• PS1: Transcript NM_000061.3 (BTK) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 376203
• PM1: In a domain Protein kinase (size 253) in uniprot entity BTK_HUMAN there are 114 pathogenic changes around while only 7 benign (94%) 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, 0.869
• PP5: Variant X-101356177-A-T is Pathogenic according to our data. Variant chrX-101356177-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376204.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.1441T>A	p.Cys481Ser	missense_variant	Exon 15 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.1543T>A	p.Cys515Ser	missense_variant	Exon 15 of 19		NP_001274273.1
BTK	NM_001287345.2	c.1039-1483T>A		intron_variant	Intron 13 of 16		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.1441T>A	p.Cys481Ser	missense_variant	Exon 15 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Aug 18, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PM1, PM2 -

X-linked agammaglobulinemia with growth hormone deficiency Uncertain:1

Oct 25, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature as a germline variant in individuals with BTK-related conditions. ClinVar contains an entry for this variant (Variation ID: 376204). This sequence change replaces cysteine with serine at codon 481 of the BTK protein (p.Cys481Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;.;D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.074	D
MutationAssessor	Benign	-1.3	.;.;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.0	.;.;D
REVEL	Uncertain	0.56
Sift	Benign	0.31	.;.;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.98	.;.;D
Vest4		0.77
MutPred		0.64		Loss of catalytic residue at L482 (P = 0.0168);.;Loss of catalytic residue at L482 (P = 0.0168);
MVP		0.95
MPC		2.6
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057519826; hg19: chrX-100611165; COSMIC: COSV58117871; COSMIC: COSV58117871;