rs754194693

chr10-63198604-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032776.3(JMJD1C):c.5400G>T(p.Glu1800Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,452,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: JMJD1C NM_032776.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052123904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JMJD1C	NM_032776.3	c.5400G>T	p.Glu1800Asp	missense_variant	12/26	ENST00000399262.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JMJD1C	ENST00000399262.7	c.5400G>T	p.Glu1800Asp	missense_variant	12/26	5	NM_032776.3
JMJD1C	ENST00000542921.5	c.4854G>T	p.Glu1618Asp	missense_variant	11/25	1		P1
JMJD1C	ENST00000402544.5	n.5170G>T		non_coding_transcript_exon_variant	8/22	1
JMJD1C	ENST00000327520.7	c.1132-1041G>T		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248536 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1452106 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 723108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.0000166 AC: 2

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

Invitae

Aug 31, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	16
Dann	Benign	0.94
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.62
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.052	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.83	D;D;D;D
PrimateAI	Uncertain	0.55	T
Polyphen		0.0010	.;B;.
Vest4		0.15, 0.13
MutPred		0.38		.;Loss of methylation at K1803 (P = 0.0814);.;
MVP		0.68
MPC		1.2
ClinPred		0.030	T
GERP RS		-0.39
Varity_R		0.047
gMVP		0.74

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: rs754194693; hg19: chr10-64958364;