chr14-23571852-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001146028.2(JPH4):​c.1220G>A​(p.Arg407Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,613,066 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: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

JPH4
NM_001146028.2 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.13030812).
BS2
High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
JPH4NM_001146028.2 linkuse as main transcriptc.1220G>A p.Arg407Gln missense_variant 4/6 ENST00000356300.9 NP_001139500.1 Q96JJ6
JPH4NM_032452.3 linkuse as main transcriptc.1220G>A p.Arg407Gln missense_variant 5/7 NP_115828.2 Q96JJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
JPH4ENST00000356300.9 linkuse as main transcriptc.1220G>A p.Arg407Gln missense_variant 4/61 NM_001146028.2 ENSP00000348648.4 Q96JJ6
JPH4ENST00000397118.7 linkuse as main transcriptc.1220G>A p.Arg407Gln missense_variant 5/71 ENSP00000380307.3 Q96JJ6
JPH4ENST00000544177.1 linkuse as main transcriptc.215G>A p.Arg72Gln missense_variant 2/42 ENSP00000439562.1 F5H1L9

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000235
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000838
AC:
21
AN:
250598
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135536
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:
0.0000478
Gnomad NFE exome
AF:
0.000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000151
AC:
221
AN:
1460784
Hom.:
0
Cov.:
32
AF XY:
0.000165
AC XY:
120
AN XY:
726778
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:
0.0000572
Gnomad4 NFE exome
AF:
0.000190
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152282
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000235
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000228
Hom.:
0
Bravo
AF:
0.000136
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000988
AC:
12
EpiCase
AF:
0.000491
EpiControl
AF:
0.000297

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 submitterclinical testingAmbry GeneticsOct 18, 2021The c.1220G>A (p.R407Q) alteration is located in exon 5 (coding exon 3) of the JPH4 gene. This alteration results from a G to A substitution at nucleotide position 1220, causing the arginine (R) at amino acid position 407 to be replaced by a glutamine (Q). 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
0.14
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.28
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.030
.;T;T;.
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.78
T;.;T;T
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.13
T;T;T;T
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
0.69
.;N;N;.
MutationTaster
Benign
0.97
D;D;D;D
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-1.0
.;N;N;D
REVEL
Benign
0.11
Sift
Benign
0.33
.;T;T;D
Sift4G
Benign
0.55
T;T;T;D
Polyphen
1.0, 1.0
.;D;D;D
Vest4
0.27
MVP
0.76
MPC
0.16
ClinPred
0.30
T
GERP RS
5.2
Varity_R
0.10
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs201428906; hg19: chr14-24041061; COSMIC: COSV58112013; COSMIC: COSV58112013; API