10-63214788-A-G

Variant names:

• chr10-63214788-A-G
• rs151186255
• NM_032776.3:c.1379T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• 22q11.2 deletion syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Illumina
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1287 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032776.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JMJD1C	NM_032776.3	MANE Select	c.1379T>C	p.Met460Thr	missense	Exon 8 of 26	NP_116165.1
	JMJD1C	NM_001322252.2		c.1265T>C	p.Met422Thr	missense	Exon 7 of 25	NP_001309181.1
	JMJD1C	NM_001282948.2		c.833T>C	p.Met278Thr	missense	Exon 7 of 25	NP_001269877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JMJD1C	ENST00000399262.7	TSL:5 MANE Select	c.1379T>C	p.Met460Thr	missense	Exon 8 of 26	ENSP00000382204.2
	JMJD1C	ENST00000542921.5	TSL:1	c.833T>C	p.Met278Thr	missense	Exon 7 of 25	ENSP00000444682.1
	JMJD1C	ENST00000402544.5	TSL:1	n.1351T>C		non_coding_transcript_exon	Exon 5 of 22

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

GnomAD2 exomes AF: 0.0114 AC: 2838 AN: 248852 AF XY: 0.0108

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 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

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26132

East Asian (EAS) AF: 0.0395 AC: 1566 AN: 39682

South Asian (SAS) AF: 0.000475 AC: 41 AN: 86250

European-Finnish (FIN) AF: 0.0809 AC: 4311 AN: 53314

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000523 AC: 581 AN: 1111788

Other (OTH) AF: 0.00462 AC: 279 AN: 60380

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

African (AFR) AF: 0.0000964 AC: 4 AN: 41494

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.0375 AC: 194 AN: 5176

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4820

European-Finnish (FIN) AF: 0.0918 AC: 972 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00137 AC: 93 AN: 68010

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00291 Hom.: 14

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.63
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.035
Sift	Benign	0.44	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.17
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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