rs188520171

chr10-63207283-C-Gchr10-63207283-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.4386G>C(p.Lys1462Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,613,794 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. K1462K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (6 hom.)
• Consequence: JMJD1C NM_032776.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.131

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=0.0067736506).
• BP6: Variant 10-63207283-C-G is Benign according to our data. Variant chr10-63207283-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 460248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JMJD1C	NM_032776.3	c.4386G>C	p.Lys1462Asn	missense_variant	10/26	ENST00000399262.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JMJD1C	ENST00000399262.7	c.4386G>C	p.Lys1462Asn	missense_variant	10/26	5	NM_032776.3
JMJD1C	ENST00000542921.5	c.3840G>C	p.Lys1280Asn	missense_variant	9/25	1		P1
JMJD1C	ENST00000402544.5	n.4358G>C		non_coding_transcript_exon_variant	7/22	1
JMJD1C	ENST00000327520.7	c.444G>C	p.Lys148Asn	missense_variant	1/12	2

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00500

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000547 AC: 136 AN: 248834 Hom.: 1 AF XY: 0.000496 AC XY: 67 AN XY: 135048

Gnomad AFR exome AF: 0.000389

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00634

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000199 AC: 291 AN: 1461468 Hom.: 6 Cov.: 33 AF XY: 0.000177 AC XY: 129 AN XY: 727068

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00363

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00210

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74486

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00501

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000431

ESP6500AA AF: 0.000999 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000537 AC: 65

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

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

Apr 27, 2022

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). -

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	0.21
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	11
Dann	Uncertain	0.99
Eigen	Benign	-0.055
Eigen_PC	Benign	-0.050
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.0068	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.41	T
Polyphen		0.070	.;B;.
Vest4		0.25, 0.24
MutPred		0.19		.;Loss of ubiquitination at K1462 (P = 0.003);.;
MVP		0.72
MPC		0.15
ClinPred		0.016	T
GERP RS		0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
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: rs188520171; hg19: chr10-64967043;