rs71508957

chr10-63168077-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_032776.3(JMJD1C):c.7591G>A(p.Glu2531Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00696 in 1,603,916 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E2531E) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0047 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (55 hom.)
• Consequence: JMJD1C NM_032776.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.64

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004607469).
• BP6: Variant 10-63168077-C-T is Benign according to our data. Variant chr10-63168077-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 460278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-63168077-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 715 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JMJD1C	NM_032776.3	c.7591G>A	p.Glu2531Lys	missense_variant	26/26	ENST00000399262.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JMJD1C	ENST00000399262.7	c.7591G>A	p.Glu2531Lys	missense_variant	26/26	5	NM_032776.3
JMJD1C	ENST00000542921.5	c.7045G>A	p.Glu2349Lys	missense_variant	25/25	1		P1
JMJD1C	ENST00000402544.5	n.7282G>A		non_coding_transcript_exon_variant	22/22	1
JMJD1C	ENST00000467356.5	n.449G>A		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes AF: 0.00470 AC: 715 AN: 152116 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00824

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00421 AC: 1047 AN: 248660 Hom.: 7 AF XY: 0.00435 AC XY: 587 AN XY: 134970

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.000895

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00298

Gnomad FIN exome AF: 0.00165

Gnomad NFE exome AF: 0.00676

Gnomad OTH exome AF: 0.00696

GnomAD4 exome AF: 0.00720 AC: 10445 AN: 1451682 Hom.: 55 Cov.: 28 AF XY: 0.00699 AC XY: 5055 AN XY: 722820

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00291

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.00860

Gnomad4 OTH exome AF: 0.00689

GnomAD4 genome AF: 0.00469 AC: 714 AN: 152234 Hom.: 6 Cov.: 32 AF XY: 0.00417 AC XY: 310 AN XY: 74428

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00822

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00632 Hom.: 9

Bravo AF: 0.00488

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00161 AC: 6

ESP6500EA AF: 0.0100 AC: 82

ExAC AF: 0.00411 AC: 496

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.00710

EpiControl AF: 0.00682

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

JMJD1C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

JMJD1C: BS2 -

Early myoclonic encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D
MetaRNN	Benign	0.0046	T;T;T
MetaSVM	Benign	-0.49	T
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.59	T
Polyphen		1.0	.;D;.
Vest4		0.63, 0.61
MVP		0.65
MPC		2.0
ClinPred		0.018	T
GERP RS		5.4
Varity_R		0.30
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

Other links and lift over

dbSNP: rs71508957; hg19: chr10-64927837; COSMIC: COSV101232265;