1-227733487-G-A

Variant names:

• chr1-227733487-G-A
• rs959492544
• NM_023007.3:c.749C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_023007.3(JMJD4):​c.749C>T​(p.Pro250Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000554 in 1,442,802 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: JMJD4 NM_023007.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JMJD4	NM_023007.3	c.749C>T	p.Pro250Leu	missense_variant	Exon 4 of 6	ENST00000620518.5	NP_075383.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JMJD4	ENST00000620518.5	c.749C>T	p.Pro250Leu	missense_variant	Exon 4 of 6	1	NM_023007.3	ENSP00000477669.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000425 AC: 1 AN: 235232 Hom.: 0 AF XY: 0.00000782 AC XY: 1 AN XY: 127936

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: 0.00000941

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000554 AC: 8 AN: 1442802 Hom.: 0 Cov.: 32 AF XY: 0.00000698 AC XY: 5 AN XY: 716090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000243

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: 0.00000635

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.887C>T (p.P296L) alteration is located in exon 4 (coding exon 4) of the JMJD4 gene. This alteration results from a C to T substitution at nucleotide position 887, causing the proline (P) at amino acid position 296 to be replaced by a leucine (L). 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	0.15
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Benign	0.87
DEOGEN2	Benign	0.054	T;T;T;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.61	.;T;T;T
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.4	M;M;.;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	N;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.57	T;.;.;.
Sift4G	Benign	0.55	T;T;T;T
Polyphen		0.061	B;B;.;B
Vest4		0.80
MutPred		0.59		Gain of stability (P = 0.0098);Gain of stability (P = 0.0098);.;Gain of stability (P = 0.0098);
MVP		0.66
MPC		0.15
ClinPred		0.42	T
GERP RS		4.5
Varity_R		0.091
gMVP		0.72

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

Other links and lift over

dbSNP: rs959492544; hg19: chr1-227921188;