16-87649169-T-G

Variant names:

• chr16-87649169-T-G
• rs748554
• NM_020655.4:c.1160+4134T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020655.4(JPH3):​c.1160+4134T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 152,134 control chromosomes in the GnomAD database, including 23,914 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 0.56 (23914 hom., cov: 34)
• Consequence: JPH3 NM_020655.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.289
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JPH3	NM_020655.4	c.1160+4134T>G		intron_variant	Intron 2 of 4	ENST00000284262.3	NP_065706.2
JPH3	NR_073379.3	n.874+4134T>G		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JPH3	ENST00000284262.3	c.1160+4134T>G		intron_variant	Intron 2 of 4	1	NM_020655.4	ENSP00000284262.2
JPH3	ENST00000537256.5	n.874+4134T>G		intron_variant	Intron 2 of 5	2

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84520 AN: 152016 Hom.: 23878 Cov.: 34

Gnomad AFR AF: 0.601

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.679

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.541

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.560

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.556 AC: 84611 AN: 152134 Hom.: 23914 Cov.: 34 AF XY: 0.563 AC XY: 41863 AN XY: 74376

African (AFR) AF: 0.602 AC: 24981 AN: 41522

American (AMR) AF: 0.642 AC: 9818 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1767 AN: 3470

East Asian (EAS) AF: 0.680 AC: 3509 AN: 5164

South Asian (SAS) AF: 0.619 AC: 2986 AN: 4826

European-Finnish (FIN) AF: 0.541 AC: 5742 AN: 10604

Middle Eastern (MID) AF: 0.531 AC: 155 AN: 292

European-Non Finnish (NFE) AF: 0.501 AC: 34016 AN: 67932

Other (OTH) AF: 0.563 AC: 1187 AN: 2110

Alfa AF: 0.406 Hom.: 1133

Bravo AF: 0.566

Asia WGS AF: 0.669 AC: 2322 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	8.1
DANN	Benign	0.72
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs748554; hg19: chr16-87682775;