rs201112543

Positions:

• chr10-63465607-A-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.56T>A​(p.Val19Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000436 in 1,609,330 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. V19V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: JMJD1C NM_032776.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.491

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-AS1 (HGNC:28222): (JMJD1C antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060442984).
• BP6: Variant 10-63465607-A-T is Benign according to our data. Variant chr10-63465607-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 460261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 349 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JMJD1C	NM_032776.3	c.56T>A	p.Val19Asp	missense_variant	1/26	ENST00000399262.7
JMJD1C-AS1	NR_027182.1	n.379A>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JMJD1C	ENST00000399262.7	c.56T>A	p.Val19Asp	missense_variant	1/26	5	NM_032776.3
JMJD1C-AS1	ENST00000609436.1	n.379A>T		non_coding_transcript_exon_variant	1/1
JMJD1C	ENST00000633035.1	n.113+56131T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 352 AN: 151890 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000580 AC: 139 AN: 239512 Hom.: 0 AF XY: 0.000442 AC XY: 58 AN XY: 131194

Gnomad AFR exome AF: 0.00868

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000929

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000242 AC: 352 AN: 1457322 Hom.: 2 Cov.: 36 AF XY: 0.000186 AC XY: 135 AN XY: 725270

Gnomad4 AFR exome AF: 0.00920

Gnomad4 AMR exome AF: 0.000224

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: 0.00000270

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.00230 AC: 349 AN: 152008 Hom.: 2 Cov.: 33 AF XY: 0.00206 AC XY: 153 AN XY: 74304

Gnomad4 AFR AF: 0.00786

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000417 Hom.: 0

Bravo AF: 0.00255

ESP6500AA AF: 0.00667 AC: 29

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000701 AC: 85

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

JMJD1C-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2019

This variant is classified as 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 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Benign	0.72
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.76	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.056
Sift	Benign	0.15	T
Sift4G	Benign	0.067	T
Polyphen		0.23	B
Vest4		0.28
MVP		0.37
MPC		0.11
ClinPred		0.031	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.10
gMVP		0.41

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: rs201112543; hg19: chr10-65225367;