10-63189165-C-T

Position:

• chr10-63189165-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_032776.3(JMJD1C):​c.6570+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,602,552 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (25 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (18 hom.)
• Consequence: JMJD1C NM_032776.3 splice_region, intron
• Scores: Splicing: ADA: 0.0002964
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.689

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 10-63189165-C-T is Benign according to our data. Variant chr10-63189165-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 460269.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 = 0.00955 (1454/152290) while in subpopulation AFR AF= 0.0332 (1381/41546). AF 95% confidence interval is 0.0318. There are 25 homozygotes in gnomad4. There are 657 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1454 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JMJD1C	NM_032776.3	c.6570+3G>A		splice_region_variant, intron_variant		ENST00000399262.7	NP_116165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JMJD1C	ENST00000399262.7	c.6570+3G>A		splice_region_variant, intron_variant		5	NM_032776.3	ENSP00000382204.2
JMJD1C	ENST00000542921.5	c.6024+3G>A		splice_region_variant, intron_variant		1		ENSP00000444682.1
JMJD1C	ENST00000402544.5	n.6286+3G>A		splice_region_variant, intron_variant		1
JMJD1C	ENST00000327520.7	c.2208+3G>A		splice_region_variant, intron_variant		2		ENSP00000335929.5

Frequencies

GnomAD3 genomes AF: 0.00951 AC: 1447 AN: 152172 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0332

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00248 AC: 597 AN: 240820 Hom.: 9 AF XY: 0.00175 AC XY: 229 AN XY: 130824

Gnomad AFR exome AF: 0.0344

Gnomad AMR exome AF: 0.00175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000345

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000456

Gnomad OTH exome AF: 0.00104

GnomAD4 exome AF: 0.000925 AC: 1342 AN: 1450262 Hom.: 18 Cov.: 30 AF XY: 0.000774 AC XY: 558 AN XY: 721000

Gnomad4 AFR exome AF: 0.0344

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000355

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000190

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00955 AC: 1454 AN: 152290 Hom.: 25 Cov.: 32 AF XY: 0.00882 AC XY: 657 AN XY: 74462

Gnomad4 AFR AF: 0.0332

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.000424 Hom.: 1

Bravo AF: 0.0109

Asia WGS AF: 0.00174 AC: 6 AN: 3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Apr 14, 2022

JMJD1C NM_032776.2 intron 18 c.6570+3G>A:This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 3.3% (1374/41424) including 24 homozygotes (https://gnomad.broadinstitute.org/variant/10-63189165-C-T?dataset=gnomad_r3). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Although this variant occurs in the splice region, computational prediction tools do not suggest that it alters splicing. However, further studies are needed to understand its impact. This variant is present in ClinVar (Variation ID:460269). In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

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
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.038
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: rs76935733; hg19: chr10-64948925;