16-87603396-A-G

Position:

• chr16-87603396-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020655.4(JPH3):​c.250A>G​(p.Lys84Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,447,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: JPH3 NM_020655.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.37

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27916834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JPH3	NM_020655.4	c.250A>G	p.Lys84Glu	missense_variant	1/5	ENST00000284262.3	NP_065706.2
JPH3	NM_001271604.4	c.250A>G	p.Lys84Glu	missense_variant	1/2		NP_001258533.1
JPH3	NM_001271605.3	c.250A>G	p.Lys84Glu	missense_variant	1/2		NP_001258534.1
JPH3	NR_073379.3	n.96+1466A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JPH3	ENST00000284262.3	c.250A>G	p.Lys84Glu	missense_variant	1/5	1	NM_020655.4	ENSP00000284262.2
JPH3	ENST00000301008.5	n.510A>G		non_coding_transcript_exon_variant	1/2	1
JPH3	ENST00000537256.5	n.96+1466A>G		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447932 Hom.: 0 Cov.: 32 AF XY: 0.00000417 AC XY: 3 AN XY: 719410

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000330 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2024

The c.250A>G (p.K84E) alteration is located in exon 1 (coding exon 1) of the JPH3 gene. This alteration results from a A to G substitution at nucleotide position 250, causing the lysine (K) at amino acid position 84 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.95	N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.0080	B
Vest4		0.44
MutPred		0.45		Loss of MoRF binding (P = 0.0039);
MVP		0.58
MPC		2.6
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.53
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs1225195549; hg19: chr16-87637002;