16-87603475-C-T

Position:

• chr16-87603475-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020655.4(JPH3):​c.329C>T​(p.Thr110Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,404,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: JPH3 NM_020655.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.27

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JPH3	NM_020655.4	c.329C>T	p.Thr110Ile	missense_variant	1/5	ENST00000284262.3	NP_065706.2
JPH3	NM_001271604.4	c.329C>T	p.Thr110Ile	missense_variant	1/2		NP_001258533.1
JPH3	NM_001271605.3	c.329C>T	p.Thr110Ile	missense_variant	1/2		NP_001258534.1
JPH3	NR_073379.3	n.96+1545C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JPH3	ENST00000284262.3	c.329C>T	p.Thr110Ile	missense_variant	1/5	1	NM_020655.4	ENSP00000284262.2
JPH3	ENST00000301008.5	n.589C>T		non_coding_transcript_exon_variant	1/2	1
JPH3	ENST00000537256.5	n.96+1545C>T		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000285 AC: 4 AN: 1404982 Hom.: 0 Cov.: 32 AF XY: 0.00000432 AC XY: 3 AN XY: 693756

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: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000277

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Feb 27, 2024

The c.329C>T (p.T110I) alteration is located in exon 1 (coding exon 1) of the JPH3 gene. This alteration results from a C to T substitution at nucleotide position 329, causing the threonine (T) at amino acid position 110 to be replaced by an isoleucine (I). 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	0.73
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	0.063
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.79	N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.014	D
Polyphen		0.073	B
Vest4		0.52
MutPred		0.45		Loss of disorder (P = 0.0517);
MVP		0.55
MPC		1.5
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.79
gMVP		0.67

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: rs2030346391; hg19: chr16-87637081;