rs1386621585

Variant names:

• chrX-101358650-T-C
• rs1386621585
• NM_000061.3:c.941A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP2

The NM_000061.3(BTK):​c.941A>G​(p.Lys314Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000165 in 1,209,192 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.83

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain SH2 (size 96) in uniprot entity BTK_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000061.3
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.941A>G	p.Lys314Arg	missense_variant	Exon 11 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.1043A>G	p.Lys348Arg	missense_variant	Exon 11 of 19		NP_001274273.1
BTK	NM_001287345.2	c.941A>G	p.Lys314Arg	missense_variant	Exon 12 of 17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.941A>G	p.Lys314Arg	missense_variant	Exon 11 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111706 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33884

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000950

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097486 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362850

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111706 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33884

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000950

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency Uncertain:1

Mar 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 314 of the BTK protein (p.Lys314Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BTK-related conditions. ClinVar contains an entry for this variant (Variation ID: 461819). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BTK protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;.;.;D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;D;T;T
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.9	.;.;.;L
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.97	.;N;.;N
REVEL	Uncertain	0.43
Sift	Benign	0.37	.;T;.;T
Sift4G	Benign	0.47	T;T;T;T
Polyphen		0.97, 1.0	.;D;.;D
Vest4		0.27
MutPred		0.25		Gain of MoRF binding (P = 0.0654);Gain of MoRF binding (P = 0.0654);.;Gain of MoRF binding (P = 0.0654);
MVP		0.97
MPC		2.4
ClinPred		0.81	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.79

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: rs1386621585; hg19: chrX-100613638;