rs927398945

Variant names:

• chr10-63189430-C-T
• rs927398945
• NM_032776.3:c.6308G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_032776.3(JMJD1C):​c.6308G>A​(p.Arg2103Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,611,360 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: JMJD1C NM_032776.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.89

Genes affected

JMJD1C (HGNC:12313): (jumonji domain containing 1C) The protein encoded by this gene interacts with thyroid hormone receptors and contains a jumonji domain. It is a candidate histone demethylase and is thought to be a coactivator for key transcription factors. It plays a role in the DNA-damage response pathway by demethylating the mediator of DNA damage checkpoint 1 (MDC1) protein, and is required for the survival of acute myeloid leukemia. Mutations in this gene are associated with Rett syndrome and intellectual disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JMJD1C	NM_032776.3	c.6308G>A	p.Arg2103Gln	missense_variant	Exon 18 of 26	ENST00000399262.7	NP_116165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JMJD1C	ENST00000399262.7	c.6308G>A	p.Arg2103Gln	missense_variant	Exon 18 of 26	5	NM_032776.3	ENSP00000382204.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459302 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725920

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.0000676

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74272

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.000155

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Oct 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6308G>A (p.R2103Q) alteration is located in exon 18 (coding exon 18) of the JMJD1C gene. This alteration results from a G to A substitution at nucleotide position 6308, causing the arginine (R) at amino acid position 2103 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Early myoclonic encephalopathy Uncertain:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2103 of the JMJD1C protein (p.Arg2103Gln). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with JMJD1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 568415). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt JMJD1C protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.033	.;T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.1	.;M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.2	.;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0060	.;D;D
Sift4G	Uncertain	0.011	.;D;D
Polyphen		1.0	.;D;.
Vest4		0.53, 0.45
MutPred		0.37		.;Gain of ubiquitination at K2100 (P = 0.0719);.;
MVP		0.67
MPC		0.54
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.42
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs927398945; hg19: chr10-64949190; COSMIC: COSV59514528; COSMIC: COSV59514528;