rs41274068

Positions:

• chr10-63214218-G-A
• chr10-63214218-G-C

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.1949C>T​(p.Thr650Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,613,936 control chromosomes in the GnomAD database, including 161 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 0.0086 (9 hom., cov: 32)
  • Exomes 𝑓: 0.012 (152 hom.)
• Consequence: JMJD1C NM_032776.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.27

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00345847).
• BP6: Variant 10-63214218-G-A is Benign according to our data. Variant chr10-63214218-G-A is described in ClinVar as [Benign]. Clinvar id is 460226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-63214218-G-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 1310 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JMJD1C	NM_032776.3	c.1949C>T	p.Thr650Ile	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.1949C>T	p.Thr650Ile	missense_variant	8/26	5	NM_032776.3	ENSP00000382204
JMJD1C	ENST00000542921.5	c.1403C>T	p.Thr468Ile	missense_variant	7/25	1		ENSP00000444682	P1
JMJD1C	ENST00000402544.5	n.1921C>T		non_coding_transcript_exon_variant	5/22	1

Frequencies

GnomAD3 genomes AF: 0.00864 AC: 1314 AN: 152160 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0177

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00874 AC: 2178 AN: 249102 Hom.: 15 AF XY: 0.00878 AC XY: 1187 AN XY: 135130

Gnomad AFR exome AF: 0.00239

Gnomad AMR exome AF: 0.00333

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00304

Gnomad FIN exome AF: 0.0185

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.00909

GnomAD4 exome AF: 0.0123 AC: 17906 AN: 1461658 Hom.: 152 Cov.: 33 AF XY: 0.0120 AC XY: 8705 AN XY: 727142

Gnomad4 AFR exome AF: 0.00251

Gnomad4 AMR exome AF: 0.00344

Gnomad4 ASJ exome AF: 0.00429

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00325

Gnomad4 FIN exome AF: 0.0174

Gnomad4 NFE exome AF: 0.0142

Gnomad4 OTH exome AF: 0.00954

GnomAD4 genome AF: 0.00860 AC: 1310 AN: 152278 Hom.: 9 Cov.: 32 AF XY: 0.00880 AC XY: 655 AN XY: 74454

Gnomad4 AFR AF: 0.00294

Gnomad4 AMR AF: 0.00360

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0177

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0111 Hom.: 17

Bravo AF: 0.00773

TwinsUK AF: 0.0181 AC: 67

ALSPAC AF: 0.0135 AC: 52

ESP6500AA AF: 0.00266 AC: 10

ESP6500EA AF: 0.0132 AC: 108

ExAC AF: 0.00858 AC: 1037

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	JMJD1C: BP4, BS1, BS2 -

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	0.12
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0071	.;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.86	D;D;D
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	.;N;N
REVEL	Benign	0.022
Sift	Uncertain	0.020	.;D;D
Sift4G	Benign	0.21	.;T;T
Polyphen		0.12	.;B;.
Vest4		0.18, 0.19
MVP		0.36
MPC		0.085
ClinPred		0.0081	T
GERP RS		3.1
Varity_R		0.034
gMVP		0.10

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: rs41274068; hg19: chr10-64973978; COSMIC: COSV99062895; COSMIC: COSV99062895;