chr1-227733487-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023007.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JMJD4	NM_023007.3	MANE Select	c.749C>T	p.Pro250Leu	missense	Exon 4 of 6	NP_075383.3	Q9H9V9-3
	JMJD4	NM_001161465.2		c.749C>T	p.Pro250Leu	missense	Exon 4 of 6	NP_001154937.2	Q9H9V9-2
	SNAP47	NM_001323930.2		c.-46+4701G>A		intron	N/A	NP_001310859.1	A0A087X0B7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JMJD4	ENST00000620518.5	TSL:1 MANE Select	c.749C>T	p.Pro250Leu	missense	Exon 4 of 6	ENSP00000477669.1	Q9H9V9-3
	JMJD4	ENST00000857562.1		c.767C>T	p.Pro256Leu	missense	Exon 4 of 6	ENSP00000527621.1
	JMJD4	ENST00000972391.1		c.746C>T	p.Pro249Leu	missense	Exon 4 of 6	ENSP00000642450.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000425 AC: 1 AN: 235232 AF XY: 0.00000782

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 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

African (AFR) AF: 0.00 AC: 0 AN: 32676

American (AMR) AF: 0.0000243 AC: 1 AN: 41068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25254

East Asian (EAS) AF: 0.00 AC: 0 AN: 39390

South Asian (SAS) AF: 0.00 AC: 0 AN: 84446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.00000635 AC: 7 AN: 1102586

Other (OTH) AF: 0.00 AC: 0 AN: 59478

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.30
Sift	Benign	0.57	T
Sift4G	Benign	0.55	T
Polyphen		0.061	B
Vest4		0.80
MutPred		0.59		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
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs959492544; hg19: chr1-227921188;