1-227733561-G-T

Variant names:

• chr1-227733561-G-T
• rs900756167
• NM_023007.3:c.675C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_023007.3(JMJD4):​c.675C>A​(p.Asn225Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: JMJD4 NM_023007.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38841823).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JMJD4	NM_023007.3	c.675C>A	p.Asn225Lys	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.675C>A	p.Asn225Lys	missense_variant	Exon 4 of 6	1	NM_023007.3	ENSP00000477669.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.813C>A (p.N271K) alteration is located in exon 4 (coding exon 4) of the JMJD4 gene. This alteration results from a C to A substitution at nucleotide position 813, causing the asparagine (N) at amino acid position 271 to be replaced by a lysine (K). 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	0.22
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	T;T;T;.
Eigen	Benign	0.023
Eigen_PC	Benign	-0.0048
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	.;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.8	L;L;.;L
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.3	D;.;.;.
REVEL	Benign	0.17
Sift	Uncertain	0.011	D;.;.;.
Sift4G	Uncertain	0.038	D;D;D;D
Polyphen		0.15	B;B;.;B
Vest4		0.30
MutPred		0.46		Gain of ubiquitination at N271 (P = 0.0101);Gain of ubiquitination at N271 (P = 0.0101);.;Gain of ubiquitination at N271 (P = 0.0101);
MVP		0.58
MPC		0.16
ClinPred		0.64	D
GERP RS		3.6
Varity_R		0.17
gMVP		0.49

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: rs900756167; hg19: chr1-227921262;