chr10-63213845-T-G

Variant summary

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

The NM_032776.3(JMJD1C):ā€‹c.2322A>Cā€‹(p.Leu774Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,752 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 (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000055 ( 0 hom. )

Consequence

JMJD1C
NM_032776.3 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0310
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.17661798).
BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
JMJD1CNM_032776.3 linkuse as main transcriptc.2322A>C p.Leu774Phe missense_variant 8/26 ENST00000399262.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
JMJD1CENST00000399262.7 linkuse as main transcriptc.2322A>C p.Leu774Phe missense_variant 8/265 NM_032776.3 Q15652-1
JMJD1CENST00000542921.5 linkuse as main transcriptc.1776A>C p.Leu592Phe missense_variant 7/251 P1Q15652-3
JMJD1CENST00000402544.5 linkuse as main transcriptn.2294A>C non_coding_transcript_exon_variant 5/221

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152056
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249144
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135160
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000465
Gnomad NFE exome
AF:
0.00000885
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461696
Hom.:
0
Cov.:
33
AF XY:
0.00000688
AC XY:
5
AN XY:
727160
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000630
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152056
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74266
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000227

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), LabcorpAug 10, 2020In summary, this variant has uncertain impact on JMJD1C function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with a JMJD1C-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 774 of the JMJD1C protein (p.Leu774Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.032
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.014
.;T;.
Eigen
Benign
0.17
Eigen_PC
Benign
0.13
FATHMM_MKL
Benign
0.74
D
LIST_S2
Uncertain
0.89
D;D;D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.18
T;T;T
MetaSVM
Benign
-0.58
T
MutationAssessor
Benign
1.9
.;L;.
MutationTaster
Benign
0.67
D;D;D;D
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-0.98
.;N;N
REVEL
Benign
0.17
Sift
Uncertain
0.0020
.;D;D
Sift4G
Benign
0.096
.;T;T
Polyphen
0.98
.;D;.
Vest4
0.34, 0.46
MutPred
0.12
.;Gain of phosphorylation at T772 (P = 0.1655);.;
MVP
0.41
MPC
0.24
ClinPred
0.21
T
GERP RS
0.37
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.16
gMVP
0.49

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: rs1414243223; hg19: chr10-64973605; API