chr1-227732428-C-A

Variant names:

• chr1-227732428-C-A
• NM_023007.3:c.1218G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_023007.3(JMJD4):​c.1218G>T​(p.Gln406His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: JMJD4 NM_023007.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14217526).

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.1218G>T	p.Gln406His	missense	Exon 6 of 6	NP_075383.3	Q9H9V9-3
	JMJD4	NM_001161465.2		c.1170G>T	p.Gln390His	missense	Exon 6 of 6	NP_001154937.2	Q9H9V9-2
	SNAP47	NM_001323930.2		c.-46+3642C>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.1218G>T	p.Gln406His	missense	Exon 6 of 6	ENSP00000477669.1	Q9H9V9-3
	SNAP47	ENST00000679575.1		c.-1136C>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 7	ENSP00000505941.1	A0A087X0B7
	SNAP47	ENST00000681447.1		c.-1136C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	ENSP00000505540.1	A0A087X0B7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460704 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 726654

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111890

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 33

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	Benign	0.16
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.81
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.023
Sift	Benign	0.23	T
Sift4G	Benign	0.44	T
Polyphen		0.0020	B
Vest4		0.072
MutPred		0.27		Loss of disorder (P = 0.0993)
MVP		0.14
MPC		0.12
ClinPred		0.083	T
GERP RS		1.9
Varity_R		0.024
gMVP		0.26
Mutation Taster		=90/10	polymorphism

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

hg19: chr1-227920129;