X-101390479-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001287344.2(BTK):c.71A>G(p.Glu24Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 512,948 control chromosomes in the GnomAD database, including 14,775 homozygotes. There are 42,588 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 7197 hom., 10801 hem., cov: 23)

Exomes 𝑓: 0.21 ( 7578 hom. 31787 hem. )

Consequence

BTK
NM_001287344.2 missense, splice_region

Scores

Splicing: ADA: 0.00007013

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.113

Publications

8 publications found

Variant links:

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

BTK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

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=9.4712937E-7).

BP6

Variant X-101390479-T-C is Benign according to our data. Variant chrX-101390479-T-C is described in ClinVar as Benign. ClinVar VariationId is 402436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001287344.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTK	NM_001287344.2		c.71A>G	p.Glu24Gly	missense splice_region	Exon 1 of 19	NP_001274273.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BTK	ENST00000621635.4	TSL:1	c.71A>G	p.Glu24Gly	missense splice_region	Exon 1 of 19	ENSP00000483570.1
BTK	ENST00000914420.1		c.-32A>G		splice_region	Exon 1 of 18	ENSP00000584479.1
BTK	ENST00000914420.1		c.-32A>G		5_prime_UTR	Exon 1 of 18	ENSP00000584479.1

Frequencies

GnomAD3 genomes

AF:

0.331

AC:

36929

AN:

111516

Hom.:

7190

Cov.:

show subpopulations

Gnomad AFR

AF:

0.748

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.250

Gnomad ASJ

AF:

0.152

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.410

Gnomad FIN

AF:

0.0990

Gnomad MID

AF:

0.224

Gnomad NFE

AF:

0.158

Gnomad OTH

AF:

0.276

GnomAD2 exomes

AF:

0.249

AC:

24340

AN:

97601

AF XY:

0.246

show subpopulations

Gnomad AFR exome

AF:

0.769

Gnomad AMR exome

AF:

0.294

Gnomad ASJ exome

AF:

0.147

Gnomad EAS exome

AF:

0.131

Gnomad FIN exome

AF:

0.107

Gnomad NFE exome

AF:

0.160

Gnomad OTH exome

AF:

0.212

GnomAD4 exome

AF:

0.207

AC:

83233

AN:

401377

Hom.:

7578

Cov.:

AF XY:

0.214

AC XY:

31787

AN XY:

148815

show subpopulations

African (AFR)

AF:

0.752

AC:

9398

AN:

12499

American (AMR)

AF:

0.292

AC:

7914

AN:

27075

Ashkenazi Jewish (ASJ)

AF:

0.152

AC:

2223

AN:

14658

East Asian (EAS)

AF:

0.130

AC:

3130

AN:

24108

South Asian (SAS)

AF:

0.389

AC:

14727

AN:

37841

European-Finnish (FIN)

AF:

0.106

AC:

2723

AN:

25614

Middle Eastern (MID)

AF:

0.188

AC:

561

AN:

2983

European-Non Finnish (NFE)

AF:

0.160

AC:

37304

AN:

233476

Other (OTH)

AF:

0.227

AC:

5253

AN:

23123

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

2096

4193

6289

8386

10482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

374

748

1122

1496

1870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.331

AC:

36985

AN:

111571

Hom.:

7197

Cov.:

AF XY:

0.320

AC XY:

10801

AN XY:

33787

show subpopulations

African (AFR)

AF:

0.748

AC:

22851

AN:

30547

American (AMR)

AF:

0.250

AC:

2642

AN:

10575

Ashkenazi Jewish (ASJ)

AF:

0.152

AC:

403

AN:

2650

East Asian (EAS)

AF:

0.130

AC:

460

AN:

3547

South Asian (SAS)

AF:

0.408

AC:

1090

AN:

2669

European-Finnish (FIN)

AF:

0.0990

AC:

604

AN:

6099

Middle Eastern (MID)

AF:

0.230

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.158

AC:

8379

AN:

53071

Other (OTH)

AF:

0.279

AC:

422

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

628

1255

1883

2510

3138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

344

688

1032

1376

1720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.382

Hom.:

7358

Bravo

AF:

0.361

TwinsUK

AF:

0.150

AC:

555

ALSPAC

AF:

0.159

AC:

458

ExAC

AF:

0.284

AC:

4231

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.88

BayesDel_noAF

Benign

-0.89

CADD

Benign

4.8

(source)

DANN

Benign

0.46

FATHMM_MKL

Benign

0.0021

LIST_S2

Benign

0.18

MetaRNN

Benign

9.5e-7

PhyloP100

-0.11

Vest4

0.061

GERP RS

-0.88

PromoterAI

0.015

Neutral

(source)

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000070

dbscSNV1_RF

Benign

0.0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over