10-63465501-G-C

Variant names:

• chr10-63465501-G-C
• rs754073844
• NM_032776.3:c.162C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032776.3(JMJD1C):​c.162C>G​(p.Asp54Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D54A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: JMJD1C NM_032776.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.294
• 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-AS1 (HGNC:28222): (JMJD1C antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07910049).

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.162C>G	p.Asp54Glu	missense	Exon 1 of 26	NP_116165.1	Q15652-1
	JMJD1C	NM_001322252.2		c.162C>G	p.Asp54Glu	missense	Exon 1 of 25	NP_001309181.1
	JMJD1C	NM_001318154.2		c.-379+56237C>G		intron	N/A	NP_001305083.1	Q15652-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JMJD1C	ENST00000399262.7	TSL:5 MANE Select	c.162C>G	p.Asp54Glu	missense	Exon 1 of 26	ENSP00000382204.2	Q15652-1
	JMJD1C-AS1	ENST00000609436.1	TSL:6	n.273G>C		non_coding_transcript_exon	Exon 1 of 1
	JMJD1C	ENST00000633035.1	TSL:3	n.113+56237C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000883 AC: 2 AN: 226558 AF XY: 0.00000806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000576

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000998

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450986 Hom.: 0 Cov.: 36 AF XY: 0.00000139 AC XY: 1 AN XY: 721544

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 44194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25842

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39482

South Asian (SAS) AF: 0.00 AC: 0 AN: 85518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5534

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109318

Other (OTH) AF: 0.00 AC: 0 AN: 60026

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000829 AC: 1

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	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.26	N
PhyloP100		0.29
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.11
Sift	Benign	0.85	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.20		Gain of MoRF binding (P = 0.1572)
MVP		0.50
MPC		0.064
ClinPred		0.20	T
GERP RS		4.1
PromoterAI		0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.26
Mutation Taster		=86/14	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: rs754073844; hg19: chr10-65225261;