rs763227625

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-227733551-C-G
• chr1-227733551-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 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 2 ACMG points.

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

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.685G>C	p.Asp229His	missense	Exon 4 of 6	NP_075383.3	Q9H9V9-3
	JMJD4	NM_001161465.2		c.685G>C	p.Asp229His	missense	Exon 4 of 6	NP_001154937.2	Q9H9V9-2
	SNAP47	NM_001323930.2		c.-46+4765C>G		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.685G>C	p.Asp229His	missense	Exon 4 of 6	ENSP00000477669.1	Q9H9V9-3
	JMJD4	ENST00000857562.1		c.703G>C	p.Asp235His	missense	Exon 4 of 6	ENSP00000527621.1
	JMJD4	ENST00000972391.1		c.682G>C	p.Asp228His	missense	Exon 4 of 6	ENSP00000642450.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000125 AC: 3 AN: 240888 AF XY: 0.0000152

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: 0.00

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33072

American (AMR) AF: 0.00 AC: 0 AN: 42644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25730

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109518

Other (OTH) AF: 0.0000333 AC: 2 AN: 60034

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000222786), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

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	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
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		5.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.44		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
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs763227625; hg19: chr1-227921252;