10-63215064-C-G

Variant names:

• chr10-63215064-C-G
• rs200644675
• NM_032776.3:c.1103G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032776.3(JMJD1C):​c.1103G>C​(p.Arg368Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000125 in 1,602,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R368Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: JMJD1C NM_032776.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.28
• Publications: 5 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3848858).

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.1103G>C	p.Arg368Pro	missense	Exon 8 of 26	NP_116165.1	Q15652-1
	JMJD1C	NM_001322252.2		c.989G>C	p.Arg330Pro	missense	Exon 7 of 25	NP_001309181.1
	JMJD1C	NM_001282948.2		c.557G>C	p.Arg186Pro	missense	Exon 7 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.1103G>C	p.Arg368Pro	missense	Exon 8 of 26	ENSP00000382204.2	Q15652-1
	JMJD1C	ENST00000542921.5	TSL:1	c.557G>C	p.Arg186Pro	missense	Exon 7 of 25	ENSP00000444682.1	Q15652-3
	JMJD1C	ENST00000402544.5	TSL:1	n.1075G>C		non_coding_transcript_exon	Exon 5 of 22

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450490 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 720964

African (AFR) AF: 0.0000305 AC: 1 AN: 32774

American (AMR) AF: 0.00 AC: 0 AN: 42504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25850

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.00 AC: 0 AN: 82508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5632

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108746

Other (OTH) AF: 0.00 AC: 0 AN: 60006

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152000 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74254

African (AFR) AF: 0.0000241 AC: 1 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

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	Uncertain	0.48
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.3
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.070	T
Polyphen		1.0	D
Vest4		0.62
MutPred		0.29		Loss of MoRF binding (P = 0.006)
MVP		0.41
MPC		0.45
ClinPred		0.94	D
GERP RS		5.7
Varity_R		0.41
gMVP		0.38
Mutation Taster		=57/43	polymorphism

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

Other links and lift over

dbSNP: rs200644675; hg19: chr10-64974824;