10-63214788-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_032776.3(JMJD1C):c.1379T>C(p.Met460Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00502 in 1,613,670 control chromosomes in the GnomAD database, including 270 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M460V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0085 (46 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (224 hom.)
• Consequence: JMJD1C NM_032776.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.628

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015247464).
• BP6: Variant 10-63214788-A-G is Benign according to our data. Variant chr10-63214788-A-G is described in ClinVar as [Benign]. Clinvar id is 460214.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00846 (1287/152164) while in subpopulation EAS AF= 0.0375 (194/5176). AF 95% confidence interval is 0.0332. There are 46 homozygotes in gnomad4. There are 943 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1289 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JMJD1C	NM_032776.3	c.1379T>C	p.Met460Thr	missense_variant	8/26	ENST00000399262.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JMJD1C	ENST00000399262.7	c.1379T>C	p.Met460Thr	missense_variant	8/26	5	NM_032776.3
JMJD1C	ENST00000542921.5	c.833T>C	p.Met278Thr	missense_variant	7/25	1		P1
JMJD1C	ENST00000402544.5	n.1351T>C		non_coding_transcript_exon_variant	5/22	1

Frequencies

GnomAD3 genomes AF: 0.00848 AC: 1289 AN: 152046 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.0378

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0918

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.0114 AC: 2838 AN: 248852 Hom.: 103 AF XY: 0.0108 AC XY: 1457 AN XY: 135004

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.0350

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0863

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00877

GnomAD4 exome AF: 0.00466 AC: 6811 AN: 1461506 Hom.: 224 Cov.: 33 AF XY: 0.00451 AC XY: 3280 AN XY: 727068

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.0395

Gnomad4 SAS exome AF: 0.000475

Gnomad4 FIN exome AF: 0.0809

Gnomad4 NFE exome AF: 0.000523

Gnomad4 OTH exome AF: 0.00462

GnomAD4 genome AF: 0.00846 AC: 1287 AN: 152164 Hom.: 46 Cov.: 32 AF XY: 0.0127 AC XY: 943 AN XY: 74396

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.0375

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0918

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00257 Hom.: 9

Bravo AF: 0.00173

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00183 AC: 15

ExAC AF: 0.0100 AC: 1212

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early myoclonic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	2.4
Dann	Benign	0.52
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.63	T;T;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.34	T
Polyphen		0.0	.;B;.
Vest4		0.17, 0.11
MPC		0.075
ClinPred		0.0052	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.024
gMVP		0.13

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: rs151186255; hg19: chr10-64974548; COSMIC: COSV67859358; COSMIC: COSV67859358;