rs766251480

Positions:

• chr10-63208076-C-A
• chr10-63208076-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032776.3(JMJD1C):​c.3593G>T​(p.Arg1198Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: JMJD1C NM_032776.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JMJD1C	NM_032776.3	c.3593G>T	p.Arg1198Leu	missense_variant	10/26	ENST00000399262.7	NP_116165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JMJD1C	ENST00000399262.7	c.3593G>T	p.Arg1198Leu	missense_variant	10/26	5	NM_032776.3	ENSP00000382204.2
JMJD1C	ENST00000542921.5	c.3047G>T	p.Arg1016Leu	missense_variant	9/25	1		ENSP00000444682.1
JMJD1C	ENST00000402544.5	n.3565G>T		non_coding_transcript_exon_variant	7/22	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early myoclonic encephalopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 23, 2019

This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 1198 of the JMJD1C protein (p.Arg1198Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant has not been reported in the literature in individuals with JMJD1C-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	.;T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.9	.;L;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.9	.;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	.;D;D
Sift4G	Uncertain	0.014	.;D;D
Polyphen		1.0	.;D;.
Vest4		0.92, 0.91
MutPred		0.24		.;Loss of MoRF binding (P = 0.0637);.;
MVP		0.88
MPC		0.45
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
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: rs766251480; hg19: chr10-64967836;