rs41274064

Positions:

• chr10-63193075-G-A
• chr10-63193075-G-C
• chr10-63193075-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032776.3(JMJD1C):​c.5939C>T​(p.Pro1980Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0344 in 1,613,898 control chromosomes in the GnomAD database, including 1,144 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (65 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1079 hom.)
• Consequence: JMJD1C NM_032776.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.13

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=0.0031484067).
• BP6: Variant 10-63193075-G-A is Benign according to our data. Variant chr10-63193075-G-A is described in ClinVar as [Benign]. Clinvar id is 460262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-63193075-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0241 (3662/152206) while in subpopulation NFE AF= 0.0392 (2663/68012). AF 95% confidence interval is 0.0379. There are 65 homozygotes in gnomad4. There are 1606 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3662 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JMJD1C	NM_032776.3	c.5939C>T	p.Pro1980Leu	missense_variant	16/26	ENST00000399262.7	NP_116165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JMJD1C	ENST00000399262.7	c.5939C>T	p.Pro1980Leu	missense_variant	16/26	5	NM_032776.3	ENSP00000382204

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3662 AN: 152088 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.00570

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0239

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0154

Gnomad FIN AF: 0.0143

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0392

Gnomad OTH AF: 0.0291

GnomAD3 exomes AF: 0.0253 AC: 6305 AN: 249414 Hom.: 110 AF XY: 0.0260 AC XY: 3524 AN XY: 135314

Gnomad AFR exome AF: 0.00536

Gnomad AMR exome AF: 0.0124

Gnomad ASJ exome AF: 0.0312

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0151

Gnomad FIN exome AF: 0.0179

Gnomad NFE exome AF: 0.0395

Gnomad OTH exome AF: 0.0262

GnomAD4 exome AF: 0.0355 AC: 51858 AN: 1461692 Hom.: 1079 Cov.: 31 AF XY: 0.0350 AC XY: 25455 AN XY: 727152

Gnomad4 AFR exome AF: 0.00606

Gnomad4 AMR exome AF: 0.0136

Gnomad4 ASJ exome AF: 0.0299

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0150

Gnomad4 FIN exome AF: 0.0191

Gnomad4 NFE exome AF: 0.0412

Gnomad4 OTH exome AF: 0.0327

GnomAD4 genome AF: 0.0241 AC: 3662 AN: 152206 Hom.: 65 Cov.: 32 AF XY: 0.0216 AC XY: 1606 AN XY: 74410

Gnomad4 AFR AF: 0.00568

Gnomad4 AMR AF: 0.0239

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0154

Gnomad4 FIN AF: 0.0143

Gnomad4 NFE AF: 0.0392

Gnomad4 OTH AF: 0.0288

Alfa AF: 0.0330 Hom.: 182

Bravo AF: 0.0245

TwinsUK AF: 0.0440 AC: 163

ALSPAC AF: 0.0433 AC: 167

ESP6500AA AF: 0.00607 AC: 23

ESP6500EA AF: 0.0350 AC: 289

ExAC AF: 0.0252 AC: 3040

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0382

EpiControl AF: 0.0391

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 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.0088	.;T;.
Eigen	Benign	-0.087
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T;T;T
MetaRNN	Benign	0.0031	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	.;N;.
MutationTaster	Benign	0.73	D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.24	.;N;N
REVEL	Benign	0.063
Sift	Benign	0.068	.;T;D
Sift4G	Benign	0.13	.;T;T
Polyphen		0.0	.;B;.
Vest4		0.090, 0.15
MPC		0.14
ClinPred		0.015	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.15

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: rs41274064; hg19: chr10-64952835; COSMIC: COSV105893319; COSMIC: COSV105893319;