14-23570965-A-T

Position:

• chr14-23570965-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001146028.2(JPH4):​c.1766T>A​(p.Leu589His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: JPH4 NM_001146028.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.443

Genes affected

JPH4 (HGNC:20156): (junctophilin 4) This gene encodes a member of the junctophilin family of transmembrane proteins that are involved in the formation of the junctional membrane complexes between the plasma membrane and the endoplasmic/sarcoplasmic reticulum in excitable cells. The encoded protein contains a conserved N-terminal repeat region called the membrane occupation and recognition nexus sequence that is found in other members of the junctophilin family. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.071575105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JPH4	NM_001146028.2	c.1766T>A	p.Leu589His	missense_variant	5/6	ENST00000356300.9	NP_001139500.1
JPH4	NM_032452.3	c.1766T>A	p.Leu589His	missense_variant	6/7		NP_115828.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JPH4	ENST00000356300.9	c.1766T>A	p.Leu589His	missense_variant	5/6	1	NM_001146028.2	ENSP00000348648.4
JPH4	ENST00000397118.7	c.1766T>A	p.Leu589His	missense_variant	6/7	1		ENSP00000380307.3
JPH4	ENST00000544177.1	c.761T>A	p.Leu254His	missense_variant	3/4	2		ENSP00000439562.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The c.1766T>A (p.L589H) alteration is located in exon 6 (coding exon 4) of the JPH4 gene. This alteration results from a T to A substitution at nucleotide position 1766, causing the leucine (L) at amino acid position 589 to be replaced by a histidine (H). 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	Benign	0.082
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.024	.;T;T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.54	T;.;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.072	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.89	.;N;N;D
REVEL	Benign	0.068
Sift	Benign	0.25	.;T;T;T
Sift4G	Benign	0.54	T;T;T;D
Polyphen		0.70, 0.55	.;P;P;P
Vest4		0.33
MutPred		0.16		.;Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);.;
MVP		0.43
MPC		0.36
ClinPred		0.34	T
GERP RS		-0.90
Varity_R		0.14
gMVP		0.18

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-24040174;