rs41274072

Positions:

• chr10-63214396-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032776.3(JMJD1C):​c.1771A>G​(p.Met591Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0326 in 1,613,846 control chromosomes in the GnomAD database, including 1,181 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (298 hom., cov: 32)
  • Exomes 𝑓: 0.031 (883 hom.)
• Consequence: JMJD1C NM_032776.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.355

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013146698).
• BP6: Variant 10-63214396-T-C is Benign according to our data. Variant chr10-63214396-T-C is described in ClinVar as [Benign]. Clinvar id is 460225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-63214396-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JMJD1C	NM_032776.3	c.1771A>G	p.Met591Val	missense_variant	8/26	ENST00000399262.7	NP_116165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JMJD1C	ENST00000399262.7	c.1771A>G	p.Met591Val	missense_variant	8/26	5	NM_032776.3	ENSP00000382204
JMJD1C	ENST00000542921.5	c.1225A>G	p.Met409Val	missense_variant	7/25	1		ENSP00000444682	P1
JMJD1C	ENST00000402544.5	n.1743A>G		non_coding_transcript_exon_variant	5/22	1

Frequencies

GnomAD3 genomes AF: 0.0510 AC: 7769 AN: 152220 Hom.: 293 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0278

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.0430

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0339

Gnomad OTH AF: 0.0411

GnomAD3 exomes AF: 0.0289 AC: 7204 AN: 248896 Hom.: 223 AF XY: 0.0267 AC XY: 3601 AN XY: 135032

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.00845

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00301

Gnomad FIN exome AF: 0.0435

Gnomad NFE exome AF: 0.0329

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0306 AC: 44768 AN: 1461508 Hom.: 883 Cov.: 33 AF XY: 0.0295 AC XY: 21441 AN XY: 727070

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.0163

Gnomad4 ASJ exome AF: 0.00949

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00333

Gnomad4 FIN exome AF: 0.0435

Gnomad4 NFE exome AF: 0.0319

Gnomad4 OTH exome AF: 0.0310

GnomAD4 genome AF: 0.0512 AC: 7796 AN: 152338 Hom.: 298 Cov.: 32 AF XY: 0.0498 AC XY: 3711 AN XY: 74504

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.0278

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0430

Gnomad4 NFE AF: 0.0339

Gnomad4 OTH AF: 0.0406

Alfa AF: 0.0344 Hom.: 228

Bravo AF: 0.0535

TwinsUK AF: 0.0270 AC: 100

ALSPAC AF: 0.0324 AC: 125

ESP6500AA AF: 0.107 AC: 401

ESP6500EA AF: 0.0308 AC: 254

ExAC AF: 0.0316 AC: 3816

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0290

EpiControl AF: 0.0283

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Early myoclonic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.3
DANN	Benign	0.54
DEOGEN2	Benign	0.0071	.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.64	T;T;T
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	.;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.17	.;N;N
REVEL	Benign	0.060
Sift	Benign	1.0	.;T;T
Sift4G	Benign	0.23	.;T;T
Polyphen		0.0	.;B;.
Vest4		0.031, 0.017
MPC		0.067
ClinPred		0.0058	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.019
gMVP		0.075

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41274072; hg19: chr10-64974156;