rs5991926

Variant names:

• chrX-101358637-A-G
• rs5991926
• NM_000061.3:c.954T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000061.3(BTK):​c.954T>C​(p.Ser318Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,209,071 control chromosomes in the GnomAD database, including 93 homozygotes. There are 1,212 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (50 hom., 518 hem., cov: 22)
  • Exomes 𝑓: 0.0022 (43 hom. 694 hem.)
• Consequence: BTK NM_000061.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.20
• Publications: 4 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant X-101358637-A-G is Benign according to our data. Variant chrX-101358637-A-G is described in ClinVar as Benign. ClinVar VariationId is 367695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0588 is higher than 0.05.

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.954T>C	p.Ser318Ser	synonymous	Exon 11 of 19	NP_000052.1
	BTK	NM_001287344.2		c.1056T>C	p.Ser352Ser	synonymous	Exon 11 of 19	NP_001274273.1
	BTK	NM_001287345.2		c.954T>C	p.Ser318Ser	synonymous	Exon 12 of 17	NP_001274274.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTK	ENST00000308731.8	TSL:1 MANE Select	c.954T>C	p.Ser318Ser	synonymous	Exon 11 of 19	ENSP00000308176.8
	BTK	ENST00000621635.4	TSL:1	c.1056T>C	p.Ser352Ser	synonymous	Exon 11 of 19	ENSP00000483570.1
	BTK	ENST00000944957.1		c.954T>C	p.Ser318Ser	synonymous	Exon 11 of 19	ENSP00000615016.1

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2024 AN: 111856 Hom.: 50 Cov.: 22

Gnomad AFR AF: 0.0612

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00815

Gnomad ASJ AF: 0.00416

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.000489

Gnomad OTH AF: 0.0132

GnomAD2 exomes AF: 0.00597 AC: 1096 AN: 183505 AF XY: 0.00386

Gnomad AFR exome AF: 0.0681

Gnomad AMR exome AF: 0.00365

Gnomad ASJ exome AF: 0.00574

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000403

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00224 AC: 2456 AN: 1097162 Hom.: 43 Cov.: 30 AF XY: 0.00191 AC XY: 694 AN XY: 362550

African (AFR) AF: 0.0645 AC: 1702 AN: 26368

American (AMR) AF: 0.00446 AC: 157 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00506 AC: 98 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30196

South Asian (SAS) AF: 0.000222 AC: 12 AN: 54092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40514

Middle Eastern (MID) AF: 0.0111 AC: 46 AN: 4134

European-Non Finnish (NFE) AF: 0.000199 AC: 167 AN: 841224

Other (OTH) AF: 0.00595 AC: 274 AN: 46055

GnomAD4 genome AF: 0.0181 AC: 2025 AN: 111909 Hom.: 50 Cov.: 22 AF XY: 0.0152 AC XY: 518 AN XY: 34071

African (AFR) AF: 0.0611 AC: 1880 AN: 30769

American (AMR) AF: 0.00814 AC: 86 AN: 10565

Ashkenazi Jewish (ASJ) AF: 0.00416 AC: 11 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3541

South Asian (SAS) AF: 0.00 AC: 0 AN: 2698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6075

Middle Eastern (MID) AF: 0.00926 AC: 2 AN: 216

European-Non Finnish (NFE) AF: 0.000489 AC: 26 AN: 53190

Other (OTH) AF: 0.0131 AC: 20 AN: 1531

Alfa AF: 0.0132 Hom.: 69

Bravo AF: 0.0226

EpiCase AF: 0.00104

EpiControl AF: 0.000771

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	X-linked agammaglobulinemia with growth hormone deficiency (2)
-	-	1	X-linked agammaglobulinemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	10
DANN	Benign	0.70
PhyloP100		1.2
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5991926; hg19: chrX-100613625;