rs1554829980

Variant names:

• chr10-63189251-A-C
• rs1554829980
• NM_032776.3:c.6487T>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_032776.3(JMJD1C):​c.6487T>G​(p.Cys2163Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,460,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C2163Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: JMJD1C NM_032776.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.39
• Publications: 0 publications found

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]

JMJD1C Gene-Disease associations (from GenCC):

• 22q11.2 deletion syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Illumina
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032776.3. 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
	JMJD1C	NM_032776.3	MANE Select	c.6487T>G	p.Cys2163Gly	missense	Exon 18 of 26	NP_116165.1	Q15652-1
	JMJD1C	NM_001322252.2		c.6373T>G	p.Cys2125Gly	missense	Exon 17 of 25	NP_001309181.1
	JMJD1C	NM_001282948.2		c.5941T>G	p.Cys1981Gly	missense	Exon 17 of 25	NP_001269877.1	Q15652-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JMJD1C	ENST00000399262.7	TSL:5 MANE Select	c.6487T>G	p.Cys2163Gly	missense	Exon 18 of 26	ENSP00000382204.2	Q15652-1
	JMJD1C	ENST00000542921.5	TSL:1	c.5941T>G	p.Cys1981Gly	missense	Exon 17 of 25	ENSP00000444682.1	Q15652-3
	JMJD1C	ENST00000402544.5	TSL:1	n.6203T>G		non_coding_transcript_exon	Exon 14 of 22

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460826 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726810

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111262

Other (OTH) AF: 0.0000497 AC: 3 AN: 60352

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Early myoclonic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-9.9	D
REVEL	Uncertain	0.51
Sift	Benign	0.094	T
Sift4G	Benign	0.78	T
Polyphen		0.098	B
Vest4		0.84
MutPred		0.54		Loss of stability (P = 0.0081)
MVP		0.82
MPC		0.67
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.75
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.78		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554829980; hg19: chr10-64949011;