chr10-63168056-C-G

Position:

• chr10-63168056-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032776.3(JMJD1C):​c.7612G>C​(p.Glu2538Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: JMJD1C NM_032776.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23334551).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JMJD1C	NM_032776.3	c.7612G>C	p.Glu2538Gln	missense_variant	26/26	ENST00000399262.7	NP_116165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JMJD1C	ENST00000399262.7	c.7612G>C	p.Glu2538Gln	missense_variant	26/26	5	NM_032776.3	ENSP00000382204.2
JMJD1C	ENST00000542921.5	c.7066G>C	p.Glu2356Gln	missense_variant	25/25	1		ENSP00000444682.1
JMJD1C	ENST00000402544.5	n.7303G>C		non_coding_transcript_exon_variant	22/22	1
JMJD1C	ENST00000467356.5	n.470G>C		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

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

Jul 24, 2019

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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with JMJD1C-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glutamine at codon 2538 of the JMJD1C protein (p.Glu2538Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	.;T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.9	.;M;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.94	.;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0020	.;D;D
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		1.0	.;D;.
Vest4		0.19, 0.19
MutPred		0.11		.;Loss of loop (P = 0.1258);.;
MVP		0.75
MPC		1.8
ClinPred		0.83	D
GERP RS		5.4
Varity_R		0.38
gMVP		0.30

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: rs1564539562; hg19: chr10-64927816;