Variant 8-74245139-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_020647.4(JPH1):c.1295T>C(p.Val432Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000202 in 1,604,564 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.000086 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

JPH1
NM_020647.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.63

Variant links:

Genes affected

JPH1 (HGNC:14201): (junctophilin 1) 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. This gene is a member of the junctophilin gene family. [provided by RefSeq, Jul 2008]

JPH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.058776498).

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JPH1	NM_020647.4 linkuse as main transcript	c.1295T>C	p.Val432Ala	missense_variant	4/6	ENST00000342232.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JPH1	ENST00000342232.5 linkuse as main transcript	c.1295T>C	p.Val432Ala	missense_variant	4/6	1	NM_020647.4	P1
JPH1	ENST00000519947.1 linkuse as main transcript	c.*690T>C		3_prime_UTR_variant, NMD_transcript_variant	4/5	1

Frequencies

GnomAD3 genomes

AF:

0.0000863

AC:

AN:

150566

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000661

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000950

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000218

AC:

AN:

243332

Hom.:

AF XY:

0.000197

AC XY:

AN XY:

131704

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:

0.000234

Gnomad NFE exome

AF:

0.000423

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.000214

AC:

311

AN:

1453998

Hom.:

Cov.:

AF XY:

0.000194

AC XY:

140

AN XY:

723174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000469

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000357

Gnomad4 NFE exome

AF:

0.000250

Gnomad4 OTH exome

AF:

0.000200

GnomAD4 genome

AF:

0.0000863

AC:

AN:

150566

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

73546

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000661

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000950

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000204

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000338

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

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.1295T>C (p.V432A) alteration is located in exon 4 (coding exon 4) of the JPH1 gene. This alteration results from a T to C substitution at nucleotide position 1295, causing the valine (V) at amino acid position 432 to be replaced by an alanine (A). 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

0.073

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.082

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.52

M_CAP

Benign

0.013

MetaRNN

Benign

0.059

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.3

MutationTaster

Benign

0.67

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.69

REVEL

Benign

0.091

Sift

Benign

0.26

Sift4G

Benign

0.60

Polyphen

0.012

Vest4

0.34

MVP

0.19

MPC

0.12

ClinPred

0.11

GERP RS

3.9

Varity_R

0.041

gMVP

0.34

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