rs367831647

Variant summary

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

The NM_032776.3(JMJD1C):​c.3248C>T​(p.Ser1083Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00018 in 1,613,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

JMJD1C
NM_032776.3 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.18
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]

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=0.14497891).
BS2
High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
JMJD1CNM_032776.3 linkuse as main transcriptc.3248C>T p.Ser1083Leu missense_variant 10/26 ENST00000399262.7 NP_116165.1 Q15652-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
JMJD1CENST00000399262.7 linkuse as main transcriptc.3248C>T p.Ser1083Leu missense_variant 10/265 NM_032776.3 ENSP00000382204.2 Q15652-1
JMJD1CENST00000542921.5 linkuse as main transcriptc.2702C>T p.Ser901Leu missense_variant 9/251 ENSP00000444682.1 Q15652-3
JMJD1CENST00000402544.5 linkuse as main transcriptn.3220C>T non_coding_transcript_exon_variant 7/221

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152150
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
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:
0.000235
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000723
AC:
18
AN:
249052
Hom.:
0
AF XY:
0.0000962
AC XY:
13
AN XY:
135118
show subpopulations
Gnomad AFR exome
AF:
0.000129
Gnomad AMR exome
AF:
0.00
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:
0.000133
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.000186
AC:
272
AN:
1461684
Hom.:
0
Cov.:
33
AF XY:
0.000182
AC XY:
132
AN XY:
727138
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
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:
0.000237
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152150
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000235
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000181
Hom.:
0
Bravo
AF:
0.000102
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000534
AC:
2
ESP6500EA
AF:
0.000243
AC:
2
ExAC
AF:
0.0000579
AC:
7
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 18, 2023This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1083 of the JMJD1C protein (p.Ser1083Leu). This variant is present in population databases (rs367831647, gnomAD 0.01%). 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: 576244). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on JMJD1C protein function. 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 v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.072
T
BayesDel_noAF
Benign
-0.10
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.034
.;T;.
Eigen
Benign
0.084
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.14
T;T;T
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
1.9
.;L;.
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-2.1
.;N;N
REVEL
Benign
0.21
Sift
Pathogenic
0.0
.;D;D
Sift4G
Uncertain
0.0030
.;D;D
Polyphen
0.055
.;B;.
Vest4
0.44, 0.30
MVP
0.58
MPC
0.063
ClinPred
0.20
T
GERP RS
5.6
Varity_R
0.28
gMVP
0.22

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.

Other links and lift over

dbSNP: rs367831647; hg19: chr10-64968181; API