1-227733461-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_023007.3(JMJD4):​c.775G>A​(p.Glu259Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,589,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

JMJD4
NM_023007.3 missense

Scores

9
9
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.31
Variant links:
Genes affected
JMJD4 (HGNC:25724): (jumonji domain containing 4) Enables 2-oxoglutarate-dependent dioxygenase activity. Involved in positive regulation of translational termination and protein hydroxylation. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]
SNAP47 (HGNC:30669): (synaptosome associated protein 47) Predicted to enable SNAP receptor activity and syntaxin binding activity. Predicted to be involved in synaptic vesicle fusion to presynaptic active zone membrane and synaptic vesicle priming. Predicted to act upstream of or within long-term synaptic potentiation. Colocalizes with BLOC-1 complex. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
JMJD4NM_023007.3 linkc.775G>A p.Glu259Lys missense_variant Exon 4 of 6 ENST00000620518.5 NP_075383.3 Q9H9V9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
JMJD4ENST00000620518.5 linkc.775G>A p.Glu259Lys missense_variant Exon 4 of 6 1 NM_023007.3 ENSP00000477669.1 A0A087WT84

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152214
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000217
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000433
AC:
1
AN:
231202
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
125682
show subpopulations
Gnomad AFR exome
AF:
0.0000630
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000104
AC:
15
AN:
1437482
Hom.:
0
Cov.:
32
AF XY:
0.0000112
AC XY:
8
AN XY:
713098
show subpopulations
Gnomad4 AFR exome
AF:
0.000154
Gnomad4 AMR exome
AF:
0.0000249
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:
0.00000364
Gnomad4 OTH exome
AF:
0.0000675
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152214
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.000217
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000529

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 20, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.913G>A (p.E305K) alteration is located in exon 4 (coding exon 4) of the JMJD4 gene. This alteration results from a G to A substitution at nucleotide position 913, causing the glutamic acid (E) at amino acid position 305 to be replaced by a lysine (K). 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
0.88
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.44
T;T;T;.
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.97
.;D;D;D
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Uncertain
0.56
D
MutationAssessor
Pathogenic
3.9
H;H;.;H
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-3.2
D;.;.;.
REVEL
Pathogenic
0.79
Sift
Uncertain
0.0030
D;.;.;.
Sift4G
Uncertain
0.0050
D;D;D;D
Polyphen
1.0
D;D;.;D
Vest4
0.95
MutPred
0.87
Gain of glycosylation at E305 (P = 0.086);Gain of glycosylation at E305 (P = 0.086);.;Gain of glycosylation at E305 (P = 0.086);
MVP
0.74
MPC
0.61
ClinPred
0.99
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.67
gMVP
0.91

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.

Other links and lift over

dbSNP: rs1001585426; hg19: chr1-227921162; API