Variant 14-23571250-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000356300.9(JPH4):c.1481C>T(p.Ala494Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

JPH4
ENST00000356300.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.72

Variant links:

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]

JPH4 links:

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ACMG classification

Classification made for transcript

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=0.12185502).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JPH4	NM_001146028.2 linkuse as main transcript	c.1481C>T	p.Ala494Val	missense_variant	5/6	ENST00000356300.9	NP_001139500.1	Q96JJ6
JPH4	NM_032452.3 linkuse as main transcript	c.1481C>T	p.Ala494Val	missense_variant	6/7		NP_115828.2	Q96JJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
JPH4	ENST00000356300.9 linkuse as main transcript	c.1481C>T	p.Ala494Val	missense_variant	5/6	1	NM_001146028.2	ENSP00000348648.4	Q96JJ6
JPH4	ENST00000397118.7 linkuse as main transcript	c.1481C>T	p.Ala494Val	missense_variant	6/7	1		ENSP00000380307.3	Q96JJ6
JPH4	ENST00000544177.1 linkuse as main transcript	c.476C>T	p.Ala159Val	missense_variant	3/4	2		ENSP00000439562.1	F5H1L9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000410

AC:

AN:

244148

Hom.:

AF XY:

0.00000757

AC XY:

AN XY:

132148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000914

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456626

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724216

show subpopulations

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2023

The c.1481C>T (p.A494V) alteration is located in exon 6 (coding exon 4) of the JPH4 gene. This alteration results from a C to T substitution at nucleotide position 1481, causing the alanine (A) at amino acid position 494 to be replaced by a valine (V). 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

0.090

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.017

.;T;T;.

Eigen

Benign

-0.0073

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.71

T;.;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

.;N;N;.

MutationTaster

Benign

0.88

N;N;N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.1

.;N;N;D

REVEL

Benign

0.055

Sift

Benign

0.28

.;T;T;D

Sift4G

Benign

0.29

T;T;T;D

Polyphen

0.079, 0.16

.;B;B;B

Vest4

0.26

MVP

0.37

MPC

0.17

ClinPred

0.35

GERP RS

5.2

Varity_R

0.077

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over