rs35877704

Variant names:

• chrX-101360729-C-A
• rs35877704
• NM_000061.3:c.615G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-101360729-C-A
• chrX-101360729-C-G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_000061.3(BTK):​c.615G>T​(p.Glu205Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,209,517 control chromosomes in the GnomAD database, including 1 homozygotes. There are 658 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: 𝑓 0.0011 (0 hom., 34 hem., cov: 22)
  • Exomes 𝑓: 0.0018 (1 hom. 624 hem.)
• Consequence: BTK NM_000061.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.74
• Publications: 7 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: Labcorp Genetics (formerly Invitae), ClinGen
• short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 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=0.0061905086).
• BP6: Variant X-101360729-C-A is Benign according to our data. Variant chrX-101360729-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 286327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 34 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000061.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTK	NM_000061.3	MANE Select	c.615G>T	p.Glu205Asp	missense	Exon 8 of 19	NP_000052.1	Q06187-1
	BTK	NM_001287344.2		c.717G>T	p.Glu239Asp	missense	Exon 8 of 19	NP_001274273.1	Q06187-2
	BTK	NM_001287345.2		c.615G>T	p.Glu205Asp	missense	Exon 9 of 17	NP_001274274.1	Q5JY90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTK	ENST00000308731.8	TSL:1 MANE Select	c.615G>T	p.Glu205Asp	missense	Exon 8 of 19	ENSP00000308176.8	Q06187-1
	BTK	ENST00000621635.4	TSL:1	c.717G>T	p.Glu239Asp	missense	Exon 8 of 19	ENSP00000483570.1	Q06187-2
	BTK	ENST00000944957.1		c.615G>T	p.Glu205Asp	missense	Exon 8 of 19	ENSP00000615016.1

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 126 AN: 111275 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000288

Gnomad ASJ AF: 0.00719

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00110 AC: 202 AN: 183290 AF XY: 0.000900

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000401

Gnomad ASJ exome AF: 0.00628

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000250

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00221

GnomAD4 exome AF: 0.00181 AC: 1985 AN: 1098188 Hom.: 1 Cov.: 32 AF XY: 0.00172 AC XY: 624 AN XY: 363542

African (AFR) AF: 0.000341 AC: 9 AN: 26401

American (AMR) AF: 0.000227 AC: 8 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00645 AC: 125 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.000332 AC: 18 AN: 54148

European-Finnish (FIN) AF: 0.000247 AC: 10 AN: 40533

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4137

European-Non Finnish (NFE) AF: 0.00207 AC: 1746 AN: 842076

Other (OTH) AF: 0.00139 AC: 64 AN: 46095

GnomAD4 genome AF: 0.00113 AC: 126 AN: 111329 Hom.: 0 Cov.: 22 AF XY: 0.00101 AC XY: 34 AN XY: 33525

African (AFR) AF: 0.000294 AC: 9 AN: 30615

American (AMR) AF: 0.000288 AC: 3 AN: 10431

Ashkenazi Jewish (ASJ) AF: 0.00719 AC: 19 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3548

South Asian (SAS) AF: 0.00 AC: 0 AN: 2635

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.00169 AC: 90 AN: 53105

Other (OTH) AF: 0.00332 AC: 5 AN: 1506

Alfa AF: 0.00171 Hom.: 81

Bravo AF: 0.000982

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00223 AC: 15

ExAC AF: 0.00105 AC: 128

EpiCase AF: 0.00196

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	X-linked agammaglobulinemia with growth hormone deficiency (2)
-	-	1	BTK-related disorder (1)
-	-	1	X-linked agammaglobulinemia (1)
-	-	1	X-linked agammaglobulinemia;C0472813:X-linked agammaglobulinemia with growth hormone deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.15
Sift	Benign	0.59	T
Sift4G	Benign	0.62	T
Polyphen		0.33	B
Vest4		0.036
MutPred		0.36		Loss of glycosylation at P203 (P = 0.1191)
MVP		0.85
MPC		1.2
ClinPred		0.020	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.64
Mutation Taster		=92/8	polymorphism (auto)

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: rs35877704; hg19: chrX-100615717; COSMIC: COSV58121072;