X-101349900-C-T

Variant names:

• chrX-101349900-C-T
• rs782709592
• NM_000061.3:c.1965G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 3P and 8B. PM1 PP2 BP4_Moderate BP6_Moderate BS2

The NM_000061.3(BTK):​c.1965G>A​(p.Met655Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,095,952 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.22
• Publications: 0 publications found

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]

BTK Gene-Disease associations (from GenCC):

• Bruton-type agammaglobulinemia

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, ClinGen
• isolated growth hormone deficiency type III

  Inheritance: XL Classification: STRONG, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM1: In a domain Protein kinase (size 253) in uniprot entity BTK_HUMAN there are 70 pathogenic changes around while only 6 benign (92%) in NM_000061.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. 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). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Bruton-type agammaglobulinemia, short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia, isolated growth hormone deficiency type III.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15746889).
• BP6: Variant X-101349900-C-T is Benign according to our data. Variant chrX-101349900-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3636307.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTK	NM_000061.3	c.1965G>A	p.Met655Ile	missense_variant	Exon 19 of 19	ENST00000308731.8	NP_000052.1
BTK	NM_001287344.2	c.2067G>A	p.Met689Ile	missense_variant	Exon 19 of 19		NP_001274273.1
BTK	NM_001287345.2	c.1437G>A	p.Met479Ile	missense_variant	Exon 17 of 17		NP_001274274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTK	ENST00000308731.8	c.1965G>A	p.Met655Ile	missense_variant	Exon 19 of 19	1	NM_000061.3	ENSP00000308176.8

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183449 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1095952 Hom.: 0 Cov.: 29 AF XY: 0.00000553 AC XY: 2 AN XY: 361382

African (AFR) AF: 0.00 AC: 0 AN: 26358

American (AMR) AF: 0.00 AC: 0 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19359

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54069

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40515

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840126

Other (OTH) AF: 0.00 AC: 0 AN: 45997

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked agammaglobulinemia with growth hormone deficiency Benign:1

Mar 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	.;.;T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.57	.;.;N
PhyloP100		1.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.93	N;.;N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;.;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.011	B;.;B
Vest4		0.21
MutPred		0.26		.;.;Loss of loop (P = 0.1242);
MVP		0.90
MPC		1.4
ClinPred		0.28	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.83
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs782709592; hg19: chrX-100604888;