rs34798625

Variant names:

• chr10-63215561-C-T
• rs34798625
• NM_032776.3:c.814G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032776.3(JMJD1C):​c.814G>A​(p.Ala272Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00633 in 1,608,906 control chromosomes in the GnomAD database, including 97 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (68 hom.)
• Consequence: JMJD1C NM_032776.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.525
• 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=0.0011672676).
• BP6: Variant 10-63215561-C-T is Benign according to our data. Variant chr10-63215561-C-T is described in ClinVar as Benign. ClinVar VariationId is 460281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2031/152238) while in subpopulation AFR AF = 0.0338 (1403/41534). AF 95% confidence interval is 0.0323. There are 29 homozygotes in GnomAd4. There are 984 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2031 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JMJD1C	NM_032776.3	MANE Select	c.814G>A	p.Ala272Thr	missense	Exon 6 of 26	NP_116165.1	Q15652-1
	JMJD1C	NM_001322252.2		c.700G>A	p.Ala234Thr	missense	Exon 5 of 25	NP_001309181.1
	JMJD1C	NM_001282948.2		c.268G>A	p.Ala90Thr	missense	Exon 5 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.814G>A	p.Ala272Thr	missense	Exon 6 of 26	ENSP00000382204.2	Q15652-1
	JMJD1C	ENST00000542921.5	TSL:1	c.268G>A	p.Ala90Thr	missense	Exon 5 of 25	ENSP00000444682.1	Q15652-3
	JMJD1C	ENST00000402544.5	TSL:1	n.786G>A		non_coding_transcript_exon	Exon 3 of 22

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2027 AN: 152120 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0338

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00473

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.00678 AC: 1684 AN: 248450 AF XY: 0.00653

Gnomad AFR exome AF: 0.0359

Gnomad AMR exome AF: 0.00740

Gnomad ASJ exome AF: 0.00290

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000372

Gnomad NFE exome AF: 0.00481

Gnomad OTH exome AF: 0.00647

GnomAD4 exome AF: 0.00560 AC: 8161 AN: 1456668 Hom.: 68 Cov.: 33 AF XY: 0.00557 AC XY: 4032 AN XY: 723588

African (AFR) AF: 0.0326 AC: 1086 AN: 33360

American (AMR) AF: 0.00791 AC: 352 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.00326 AC: 85 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.00864 AC: 744 AN: 86094

European-Finnish (FIN) AF: 0.000244 AC: 13 AN: 53364

Middle Eastern (MID) AF: 0.00782 AC: 45 AN: 5754

European-Non Finnish (NFE) AF: 0.00486 AC: 5387 AN: 1107812

Other (OTH) AF: 0.00746 AC: 449 AN: 60190

GnomAD4 genome AF: 0.0133 AC: 2031 AN: 152238 Hom.: 29 Cov.: 32 AF XY: 0.0132 AC XY: 984 AN XY: 74442

African (AFR) AF: 0.0338 AC: 1403 AN: 41534

American (AMR) AF: 0.0141 AC: 216 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00787 AC: 38 AN: 4830

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00474 AC: 322 AN: 68004

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.00796 Hom.: 24

Bravo AF: 0.0144

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.0328 AC: 124

ESP6500EA AF: 0.00534 AC: 44

ExAC AF: 0.00731 AC: 883

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00551

EpiControl AF: 0.00605

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Early myoclonic encephalopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.16
DANN	Benign	0.68
DEOGEN2	Benign	0.0059	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
PhyloP100		-0.53
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.71	N
REVEL	Benign	0.081
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.036
MVP		0.20
MPC		0.064
ClinPred		0.0010	T
GERP RS		-6.3
Varity_R		0.020
gMVP		0.094
Mutation Taster		=94/6	polymorphism

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: rs34798625; hg19: chr10-64975321; COSMIC: COSV67861368; COSMIC: COSV67861368;