rs41274074

Variant names:

• chr10-63214620-G-C
• rs41274074
• NM_032776.3:c.1547C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-63214620-G-C
• chr10-63214620-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032776.3(JMJD1C):​c.1547C>G​(p.Thr516Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,613,868 control chromosomes in the GnomAD database, including 2,342 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. T516A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.035 (286 hom., cov: 32)
  • Exomes 𝑓: 0.035 (2056 hom.)
• Consequence: JMJD1C NM_032776.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.31
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019951463).
• BP6: Variant 10-63214620-G-C is Benign according to our data. Variant chr10-63214620-G-C is described in ClinVar as Benign. ClinVar VariationId is 460220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JMJD1C	NM_032776.3	MANE Select	c.1547C>G	p.Thr516Ser	missense	Exon 8 of 26	NP_116165.1	Q15652-1
	JMJD1C	NM_001322252.2		c.1433C>G	p.Thr478Ser	missense	Exon 7 of 25	NP_001309181.1
	JMJD1C	NM_001282948.2		c.1001C>G	p.Thr334Ser	missense	Exon 7 of 25	NP_001269877.1	Q15652-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JMJD1C	ENST00000399262.7	TSL:5 MANE Select	c.1547C>G	p.Thr516Ser	missense	Exon 8 of 26	ENSP00000382204.2	Q15652-1
	JMJD1C	ENST00000542921.5	TSL:1	c.1001C>G	p.Thr334Ser	missense	Exon 7 of 25	ENSP00000444682.1	Q15652-3
	JMJD1C	ENST00000402544.5	TSL:1	n.1519C>G		non_coding_transcript_exon	Exon 5 of 22

Frequencies

GnomAD3 genomes AF: 0.0350 AC: 5324 AN: 152118 Hom.: 284 Cov.: 32

Gnomad AFR AF: 0.00917

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0902

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.0213

Gnomad FIN AF: 0.0319

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0534 AC: 13295 AN: 248770 AF XY: 0.0483

Gnomad AFR exome AF: 0.00899

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.270

Gnomad FIN exome AF: 0.0324

Gnomad NFE exome AF: 0.0248

Gnomad OTH exome AF: 0.0397

GnomAD4 exome AF: 0.0353 AC: 51615 AN: 1461632 Hom.: 2056 Cov.: 34 AF XY: 0.0340 AC XY: 24739 AN XY: 727140

African (AFR) AF: 0.00636 AC: 213 AN: 33476

American (AMR) AF: 0.112 AC: 5000 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 241 AN: 26132

East Asian (EAS) AF: 0.227 AC: 9000 AN: 39676

South Asian (SAS) AF: 0.0167 AC: 1442 AN: 86250

European-Finnish (FIN) AF: 0.0327 AC: 1744 AN: 53396

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5766

European-Non Finnish (NFE) AF: 0.0282 AC: 31405 AN: 1111832

Other (OTH) AF: 0.0420 AC: 2537 AN: 60384

GnomAD4 genome AF: 0.0350 AC: 5327 AN: 152236 Hom.: 286 Cov.: 32 AF XY: 0.0375 AC XY: 2792 AN XY: 74420

African (AFR) AF: 0.00914 AC: 380 AN: 41562

American (AMR) AF: 0.0900 AC: 1375 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.262 AC: 1356 AN: 5172

South Asian (SAS) AF: 0.0215 AC: 104 AN: 4826

European-Finnish (FIN) AF: 0.0319 AC: 338 AN: 10588

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

European-Non Finnish (NFE) AF: 0.0246 AC: 1671 AN: 68018

Other (OTH) AF: 0.0284 AC: 60 AN: 2114

Alfa AF: 0.0243 Hom.: 37

Bravo AF: 0.0395

TwinsUK AF: 0.0294 AC: 109

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.00924 AC: 34

ESP6500EA AF: 0.0264 AC: 215

ExAC AF: 0.0471 AC: 5690

Asia WGS AF: 0.120 AC: 414 AN: 3478

EpiCase AF: 0.0214

EpiControl AF: 0.0220

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Early myoclonic encephalopathy (1)
-	-	1	JMJD1C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.89
DEOGEN2	Benign	0.0054	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.3
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.11
Sift	Benign	0.24	T
Sift4G	Benign	0.86	T
Polyphen		0.0020	B
Vest4		0.019
MutPred		0.11		Gain of phosphorylation at T513 (P = 0.1277)
MPC		0.060
ClinPred		0.016	T
GERP RS		4.1
Varity_R		0.033
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: rs41274074; hg19: chr10-64974380; COSMIC: COSV67859351; COSMIC: COSV67859351;