dbSNP rs3212756: JAK3:c.1786+91C>A (chr19-17837038-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000215.4(JAK3):c.1786+91C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 836,798 control chromosomes in the GnomAD database, including 728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 481 hom., cov: 30)

Exomes 𝑓: 0.0055 ( 247 hom. )

Consequence

JAK3
NM_000215.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.00

Publications

4 publications found

Variant links:

Genes affected

JAK3 (HGNC:6193): (Janus kinase 3) The protein encoded by this gene is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction. It is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. Mutations in this gene are associated with autosomal SCID (severe combined immunodeficiency disease). [provided by RefSeq, Jul 2008]

JAK3 Gene-Disease associations (from GenCC):

T-B+ severe combined immunodeficiency due to JAK3 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, Orphanet

JAK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.99).

BP6

Variant 19-17837038-G-T is Benign according to our data. Variant chr19-17837038-G-T is described in ClinVar as Benign. ClinVar VariationId is 1281410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4 link	c.1786+91C>A	intron_variant	Intron 13 of 23	ENST00000458235.7	NP_000206.2	P52333-1A0A024R7M7
JAK3	NM_001440439.1 link	c.1786+91C>A	intron_variant	Intron 13 of 23		NP_001427368.1
JAK3	XM_011527991.3 link	c.1787-84C>A	intron_variant	Intron 13 of 13		XP_011526293.2
JAK3	XR_007066796.1 link	n.1836+91C>A	intron_variant	Intron 13 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7 link	c.1786+91C>A		intron_variant	Intron 13 of 23	5	NM_000215.4	ENSP00000391676.1		P52333-1

Frequencies

GnomAD3 genomes

AF:

0.0452

AC:

6498

AN:

143734

Hom.:

476

Cov.:

show subpopulations

Gnomad AFR

AF:

0.155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0195

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000464

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00987

Gnomad NFE

AF:

0.000453

Gnomad OTH

AF:

0.0350

GnomAD2 exomes

AF:

0.00905

AC:

1246

AN:

137606

AF XY:

0.00686

show subpopulations

Gnomad AFR exome

AF:

0.157

Gnomad AMR exome

AF:

0.00812

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000363

Gnomad OTH exome

AF:

0.00413

GnomAD4 exome

AF:

0.00552

AC:

3825

AN:

692956

Hom.:

247

Cov.:

AF XY:

0.00443

AC XY:

1616

AN XY:

364692

show subpopulations

African (AFR)

AF:

0.160

AC:

2866

AN:

17962

American (AMR)

AF:

0.00994

AC:

335

AN:

33714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19556

East Asian (EAS)

AF:

0.00

AC:

AN:

29432

South Asian (SAS)

AF:

0.000335

AC:

AN:

65594

European-Finnish (FIN)

AF:

0.0000250

AC:

AN:

39938

Middle Eastern (MID)

AF:

0.00653

AC:

AN:

2602

European-Non Finnish (NFE)

AF:

0.000366

AC:

165

AN:

450688

Other (OTH)

AF:

0.0125

AC:

419

AN:

33470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

184

369

553

738

922

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.0453

AC:

6520

AN:

143842

Hom.:

481

Cov.:

AF XY:

0.0441

AC XY:

3069

AN XY:

69524

show subpopulations

African (AFR)

AF:

0.156

AC:

6148

AN:

39500

American (AMR)

AF:

0.0195

AC:

267

AN:

13690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3410

East Asian (EAS)

AF:

0.00

AC:

AN:

4564

South Asian (SAS)

AF:

0.000464

AC:

AN:

4308

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8906

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000453

AC:

AN:

66280

Other (OTH)

AF:

0.0347

AC:

AN:

2018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

252

504

755

1007

1259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0267

Hom.:

Bravo

AF:

0.0496

Asia WGS

AF:

0.00982

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.15

(source)

DANN

Benign

0.69

PhyloP100

-1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over