NM_032776.3:c.1703A>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_032776.3(JMJD1C):c.1703A>T(p.Asp568Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,614,010 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D568G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 3 hom. )

Consequence

JMJD1C
NM_032776.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.542

Publications

9 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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010563701).

BP6

Variant 10-63214464-T-A is Benign according to our data. Variant chr10-63214464-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 460224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 133 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JMJD1C	NM_032776.3 link	c.1703A>T	p.Asp568Val	missense_variant	Exon 8 of 26	ENST00000399262.7	NP_116165.1	Q15652-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
JMJD1C	ENST00000399262.7 link	c.1703A>T	p.Asp568Val	missense_variant	Exon 8 of 26	5	NM_032776.3	ENSP00000382204.2	Q15652-1
JMJD1C	ENST00000542921.5 link	c.1157A>T	p.Asp386Val	missense_variant	Exon 7 of 25	1		ENSP00000444682.1	Q15652-3
JMJD1C	ENST00000402544.5 link	n.1675A>T		non_coding_transcript_exon_variant	Exon 5 of 22	1

Frequencies

GnomAD3 genomes

AF:

0.000874

AC:

133

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00159

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000944

AC:

235

AN:

248850

AF XY:

0.000933

show subpopulations

Gnomad AFR exome

AF:

0.000517

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.00159

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00159

AC:

2330

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

1103

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.00103

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000263

AC:

AN:

53282

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00195

AC:

2163

AN:

1111942

Other (OTH)

AF:

0.00151

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

125

249

374

498

623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<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:

0.000873

AC:

133

AN:

152352

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41586

American (AMR)

AF:

0.000523

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00159

AC:

108

AN:

68036

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.00110

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000541

AC:

ESP6500EA

AF:

0.00158

AC:

ExAC

AF:

0.000886

AC:

107

EpiCase

AF:

0.00207

EpiControl

AF:

0.00136

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

JMJD1C: BP4, BS2 -

Early myoclonic encephalopathy

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.019

.;T;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.76

.;N;.

PhyloP100

0.54

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.1

.;N;N

REVEL

Benign

0.029

Sift

Benign

0.13

.;T;T

Sift4G

Benign

0.30

.;T;T

Polyphen

0.014

.;B;.

Vest4

0.31, 0.26

MVP

0.38

MPC

0.094

ClinPred

0.0045

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.067

gMVP

0.25

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over