1-227733551-C-G

Variant names:

• chr1-227733551-C-G
• rs763227625
• NM_023007.3:c.685G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_023007.3(JMJD4):​c.685G>C​(p.Asp229His) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,454,438 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: JMJD4 NM_023007.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.22

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JMJD4	NM_023007.3	c.685G>C	p.Asp229His	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.685G>C	p.Asp229His	missense_variant	Exon 4 of 6	1	NM_023007.3	ENSP00000477669.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000125 AC: 3 AN: 240888 Hom.: 0 AF XY: 0.0000152 AC XY: 2 AN XY: 131214

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: 0.0000996

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454438 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 723502

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: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.823G>C (p.D275H) alteration is located in exon 4 (coding exon 4) of the JMJD4 gene. This alteration results from a G to C substitution at nucleotide position 823, causing the aspartic acid (D) at amino acid position 275 to be replaced by a histidine (H). 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	0.74
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T;T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.7	H;H;.;H
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.1	D;.;.;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.0050	D;.;.;.
Sift4G	Uncertain	0.031	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.58
MutPred		0.44		Gain of catalytic residue at D275 (P = 0.0353);Gain of catalytic residue at D275 (P = 0.0353);.;Gain of catalytic residue at D275 (P = 0.0353);
MVP		0.67
MPC		0.63
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.55
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs763227625; hg19: chr1-227921252;