Genetic Variant JPH3:p.Arg365Arg (chr16-87644970-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BS1BS2

The NM_020655.4(JPH3):c.1095C>T(p.Arg365Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0301 in 1,610,588 control chromosomes in the GnomAD database, including 902 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.023 ( 59 hom., cov: 32)

Exomes 𝑓: 0.031 ( 843 hom. )

Consequence

JPH3
NM_020655.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.254

Publications

3 publications found

Variant links:

Genes affected

JPH3 (HGNC:14203): (junctophilin 3) Junctional complexes between the plasma membrane and endoplasmic/sarcoplasmic reticulum are a common feature of all excitable cell types and mediate cross talk between cell surface and intracellular ion channels. The protein encoded by this gene is a component of junctional complexes and is composed of a C-terminal hydrophobic segment spanning the endoplasmic/sarcoplasmic reticulum membrane and a remaining cytoplasmic domain that shows specific affinity for the plasma membrane. CAG/CTG repeat expansion from normally 6-28 repeats to 40-59 repeats in the 3' UTR of this gene have been associated with Huntington disease-like 2 (HDL2). This gene is a member of the junctophilin gene family. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jul 2016]

JPH3 Gene-Disease associations (from GenCC):

Huntington disease-like 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

JPH3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP7

Synonymous conserved (PhyloP=-0.254 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0231 (3508/152182) while in subpopulation NFE AF = 0.031 (2108/67994). AF 95% confidence interval is 0.0299. There are 59 homozygotes in GnomAd4. There are 1617 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3508 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JPH3	NM_020655.4 link	c.1095C>T	p.Arg365Arg	synonymous_variant	Exon 2 of 5	ENST00000284262.3	NP_065706.2	Q8WXH2-1B4DIC1F8W9A3
JPH3	NR_073379.3 link	n.809C>T		non_coding_transcript_exon_variant	Exon 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JPH3	ENST00000284262.3 link	c.1095C>T	p.Arg365Arg	synonymous_variant	Exon 2 of 5	1	NM_020655.4	ENSP00000284262.2		Q8WXH2-1
JPH3	ENST00000537256.5 link	n.809C>T		non_coding_transcript_exon_variant	Exon 2 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.0230

AC:

3503

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0167

Gnomad AMI

AF:

0.0253

Gnomad AMR

AF:

0.0265

Gnomad ASJ

AF:

0.0343

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.00808

Gnomad FIN

AF:

0.00585

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0310

Gnomad OTH

AF:

0.0187

GnomAD2 exomes

AF:

0.0206

AC:

5025

AN:

243482

AF XY:

0.0209

show subpopulations

Gnomad AFR exome

AF:

0.0166

Gnomad AMR exome

AF:

0.0142

Gnomad ASJ exome

AF:

0.0336

Gnomad EAS exome

AF:

0.000843

Gnomad FIN exome

AF:

0.00519

Gnomad NFE exome

AF:

0.0301

Gnomad OTH exome

AF:

0.0237

GnomAD4 exome

AF:

0.0308

AC:

44923

AN:

1458406

Hom.:

843

Cov.:

AF XY:

0.0301

AC XY:

21807

AN XY:

725668

show subpopulations

African (AFR)

AF:

0.0145

AC:

487

AN:

33472

American (AMR)

AF:

0.0144

AC:

644

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0339

AC:

884

AN:

26110

East Asian (EAS)

AF:

0.000579

AC:

AN:

39694

South Asian (SAS)

AF:

0.0119

AC:

1028

AN:

86234

European-Finnish (FIN)

AF:

0.00619

AC:

311

AN:

50256

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0356

AC:

39616

AN:

1111826

Other (OTH)

AF:

0.0304

AC:

1832

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

2654

5308

7962

10616

13270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1534

3068

4602

6136

7670

<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:

0.0231

AC:

3508

AN:

152182

Hom.:

Cov.:

AF XY:

0.0217

AC XY:

1617

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0168

AC:

699

AN:

41552

American (AMR)

AF:

0.0265

AC:

405

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0343

AC:

119

AN:

3468

East Asian (EAS)

AF:

0.00156

AC:

AN:

5138

South Asian (SAS)

AF:

0.00809

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00585

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0310

AC:

2108

AN:

67994

Other (OTH)

AF:

0.0185

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

182

365

547

730

912

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0269

Hom.:

Bravo

AF:

0.0230

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0310

EpiControl

AF:

0.0299

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

1.4

(source)

DANN

Benign

0.85

PhyloP100

-0.25

Mutation Taster

=97/3

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

Computational scores

Splicing

Publications

Other links and lift over