rs34798625

Positions:

• chr10-63215561-C-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.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. 14/20 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

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=0.0011672676).
• BP6: Variant 10-63215561-C-T is Benign according to our data. Variant chr10-63215561-C-T is described in ClinVar as [Benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2031 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JMJD1C	NM_032776.3	c.814G>A	p.Ala272Thr	missense_variant	6/26	ENST00000399262.7	NP_116165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JMJD1C	ENST00000399262.7	c.814G>A	p.Ala272Thr	missense_variant	6/26	5	NM_032776.3	ENSP00000382204

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

GnomAD3 exomes AF: 0.00678 AC: 1684 AN: 248450 Hom.: 17 AF XY: 0.00653 AC XY: 880 AN XY: 134822

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 SAS exome AF: 0.00840

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

Gnomad4 AFR exome AF: 0.0326

Gnomad4 AMR exome AF: 0.00791

Gnomad4 ASJ exome AF: 0.00326

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00864

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.00486

Gnomad4 OTH exome AF: 0.00746

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

Gnomad4 AFR AF: 0.0338

Gnomad4 AMR AF: 0.0141

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00787

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00474

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00633 Hom.: 10

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

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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;T;T
MetaRNN	Benign	0.0012	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	.;N;.
MutationTaster	Benign	0.89	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.71	.;N;N
REVEL	Benign	0.081
Sift	Benign	1.0	.;T;T
Sift4G	Benign	1.0	.;T;T
Polyphen		0.0010	.;B;.
Vest4		0.036, 0.12
MVP		0.20
MPC		0.064
ClinPred		0.0010	T
GERP RS		-6.3
Varity_R		0.020
gMVP		0.094

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