NM_000061.3:c.*116A>C

Variant names:

• chrX-101349769-T-G
• rs700
• NM_000061.3:c.*116A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000061.3(BTK):​c.*116A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 611,910 control chromosomes in the GnomAD database, including 40,549 homozygotes. There are 81,115 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (6184 hom., 11436 hem., cov: 22)
  • Exomes 𝑓: 0.44 (34365 hom. 69679 hem.)
• Consequence: BTK NM_000061.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0110
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant X-101349769-T-G is Benign according to our data. Variant chrX-101349769-T-G is described in ClinVar as Benign. ClinVar VariationId is 367694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.488 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.*116A>C		3_prime_UTR	Exon 19 of 19	NP_000052.1	Q06187-1
	BTK	NM_001287344.2		c.*116A>C		3_prime_UTR	Exon 19 of 19	NP_001274273.1	Q06187-2
	BTK	NM_001287345.2		c.*116A>C		3_prime_UTR	Exon 17 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.*116A>C		3_prime_UTR	Exon 19 of 19	ENSP00000308176.8	Q06187-1
	BTK	ENST00000621635.4	TSL:1	c.*116A>C		3_prime_UTR	Exon 19 of 19	ENSP00000483570.1	Q06187-2
	BTK	ENST00000944957.1		c.*116A>C		3_prime_UTR	Exon 19 of 19	ENSP00000615016.1

Frequencies

GnomAD3 genomes AF: 0.357 AC: 39382 AN: 110247 Hom.: 6191 Cov.: 22

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.502

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.493

Gnomad OTH AF: 0.396

GnomAD4 exome AF: 0.435 AC: 218336 AN: 501610 Hom.: 34365 Cov.: 8 AF XY: 0.446 AC XY: 69679 AN XY: 156264

African (AFR) AF: 0.109 AC: 1502 AN: 13774

American (AMR) AF: 0.202 AC: 5314 AN: 26351

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 7446 AN: 13678

East Asian (EAS) AF: 0.188 AC: 5124 AN: 27191

South Asian (SAS) AF: 0.340 AC: 12136 AN: 35746

European-Finnish (FIN) AF: 0.511 AC: 19484 AN: 38096

Middle Eastern (MID) AF: 0.543 AC: 1597 AN: 2942

European-Non Finnish (NFE) AF: 0.486 AC: 154610 AN: 318042

Other (OTH) AF: 0.431 AC: 11123 AN: 25790

GnomAD4 genome AF: 0.357 AC: 39360 AN: 110300 Hom.: 6184 Cov.: 22 AF XY: 0.351 AC XY: 11436 AN XY: 32562

African (AFR) AF: 0.115 AC: 3515 AN: 30444

American (AMR) AF: 0.285 AC: 2936 AN: 10295

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1398 AN: 2619

East Asian (EAS) AF: 0.231 AC: 804 AN: 3488

South Asian (SAS) AF: 0.309 AC: 810 AN: 2622

European-Finnish (FIN) AF: 0.502 AC: 2879 AN: 5731

Middle Eastern (MID) AF: 0.514 AC: 111 AN: 216

European-Non Finnish (NFE) AF: 0.493 AC: 25975 AN: 52714

Other (OTH) AF: 0.392 AC: 589 AN: 1504

Alfa AF: 0.426 Hom.: 16460

Bravo AF: 0.331

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 (2)
-	-	2	X-linked agammaglobulinemia with growth hormone deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.7
DANN	Benign	0.55
PhyloP100		0.011
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs700; hg19: chrX-100604757; COSMIC: COSV58118204; COSMIC: COSV58118204;