Genetic Variant JMJD1C:p.Ala962Gly (chr10-63208784-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032776.3(JMJD1C):c.2885C>G(p.Ala962Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,426,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A962V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

JMJD1C
NM_032776.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.27

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06422058).

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	UniProt
JMJD1C	NM_032776.3	MANE Select	c.2885C>G	p.Ala962Gly	missense	Exon 10 of 26	NP_116165.1	Q15652-1
JMJD1C	NM_001322252.2		c.2771C>G	p.Ala924Gly	missense	Exon 9 of 25	NP_001309181.1
JMJD1C	NM_001282948.2		c.2339C>G	p.Ala780Gly	missense	Exon 9 of 25	NP_001269877.1	Q15652-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
JMJD1C	ENST00000399262.7	TSL:5 MANE Select	c.2885C>G	p.Ala962Gly	missense	Exon 10 of 26	ENSP00000382204.2	Q15652-1
JMJD1C	ENST00000542921.5	TSL:1	c.2339C>G	p.Ala780Gly	missense	Exon 9 of 25	ENSP00000444682.1	Q15652-3
JMJD1C	ENST00000402544.5	TSL:1	n.2857C>G		non_coding_transcript_exon	Exon 7 of 22

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1426956

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708440

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31394

American (AMR)

AF:

0.00

AC:

AN:

34838

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24066

East Asian (EAS)

AF:

0.00

AC:

AN:

39390

South Asian (SAS)

AF:

0.00

AC:

AN:

80186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52302

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5554

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1100346

Other (OTH)

AF:

0.00

AC:

AN:

58880

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

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Early myoclonic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0076

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.052

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.82

M_CAP

Benign

0.0049

MetaRNN

Benign

0.064

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.95

PhyloP100

1.3

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.040

REVEL

Benign

0.070

Sift

Benign

0.32

Sift4G

Benign

0.38

Polyphen

0.0

Vest4

0.15

MutPred

0.078

Gain of glycosylation at K961 (P = 0.0888)

MVP

0.36

MPC

0.067

ClinPred

0.25

GERP RS

4.2

Varity_R

0.061

gMVP

0.18

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over