10-63206844-T-C

Position:

chr10-63206844-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_032776.3(JMJD1C):c.4825A>G(p.Lys1609Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000356 in 1,601,564 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

JMJD1C
NM_032776.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.97

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.075665265).

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JMJD1C	NM_032776.3 linkuse as main transcript	c.4825A>G	p.Lys1609Glu	missense_variant	10/26	ENST00000399262.7	NP_116165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JMJD1C	ENST00000399262.7 linkuse as main transcript	c.4825A>G	p.Lys1609Glu	missense_variant	10/26	5	NM_032776.3	ENSP00000382204		Q15652-1
JMJD1C	ENST00000542921.5 linkuse as main transcript	c.4279A>G	p.Lys1427Glu	missense_variant	9/25	1		ENSP00000444682	P1	Q15652-3
JMJD1C	ENST00000402544.5 linkuse as main transcript	n.4797A>G		non_coding_transcript_exon_variant	7/22	1
JMJD1C	ENST00000327520.7 linkuse as main transcript	c.883A>G	p.Lys295Glu	missense_variant	1/12	2		ENSP00000335929

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000294

AC:

AN:

238376

Hom.:

AF XY:

0.0000232

AC XY:

AN XY:

129212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000125

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000273

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000324

AC:

AN:

1449230

Hom.:

Cov.:

AF XY:

0.0000305

AC XY:

AN XY:

720364

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000951

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000379

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Early myoclonic encephalopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 05, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt JMJD1C protein function. ClinVar contains an entry for this variant (Variation ID: 460254). This variant has not been reported in the literature in individuals affected with JMJD1C-related conditions. This variant is present in population databases (rs189704160, gnomAD 0.01%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1609 of the JMJD1C protein (p.Lys1609Glu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.020

.;T;.

Eigen

Benign

0.048

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.83

T;T;T

M_CAP

Benign

0.0078

MetaRNN

Benign

0.076

T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.4

.;L;.

MutationTaster

Benign

0.75

N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.2

.;N;N

REVEL

Benign

0.046

Sift

Benign

0.078

.;T;T

Sift4G

Benign

0.31

.;T;T

Polyphen

0.11

.;B;.

Vest4

0.26, 0.22

MVP

0.27

MPC

0.14

ClinPred

0.089

GERP RS

5.5

Varity_R

0.22

gMVP

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over