10-63198608-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_032776.3(JMJD1C):c.5396T>C(p.Ile1799Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000747 in 1,606,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. I1799K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

JMJD1C
NM_032776.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.87

Publications

0 publications found

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 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

JMJD1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21387324).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
JMJD1C	NM_032776.3	MANE Select	c.5396T>C	p.Ile1799Thr	missense	Exon 12 of 26	NP_116165.1
JMJD1C	NM_001322252.2		c.5282T>C	p.Ile1761Thr	missense	Exon 11 of 25	NP_001309181.1
JMJD1C	NM_001282948.2		c.4850T>C	p.Ile1617Thr	missense	Exon 11 of 25	NP_001269877.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
JMJD1C	ENST00000399262.7	TSL:5 MANE Select	c.5396T>C	p.Ile1799Thr	missense	Exon 12 of 26	ENSP00000382204.2
JMJD1C	ENST00000542921.5	TSL:1	c.4850T>C	p.Ile1617Thr	missense	Exon 11 of 25	ENSP00000444682.1
JMJD1C	ENST00000402544.5	TSL:1	n.5166T>C		non_coding_transcript_exon	Exon 8 of 22

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00000804

AC:

AN:

248626

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000756

AC:

AN:

1454482

Hom.:

Cov.:

AF XY:

0.00000967

AC XY:

AN XY:

724050

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33308

American (AMR)

AF:

0.0000224

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39490

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86084

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00000723

AC:

AN:

1105868

Other (OTH)

AF:

0.00

AC:

AN:

60130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000514

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.00000828

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Early myoclonic encephalopathy

Uncertain:1

Jun 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1799 of the JMJD1C protein (p.Ile1799Thr). This variant is present in population databases (rs367650429, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with JMJD1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 460259). 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 with a negative predictive value of 80%. 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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

-0.11

Eigen_PC

Benign

0.098

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.014

MetaRNN

Benign

0.21

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

5.9

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.13

Sift

Benign

0.060

Sift4G

Uncertain

0.012

Polyphen

0.015

Vest4

0.58

MVP

0.43

MPC

1.6

ClinPred

0.62

GERP RS

5.2

Varity_R

0.16

gMVP

0.68

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over