rs12780

Positions:

• chr4-80203442-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000415738.3(PRDM8):​c.1980G>C​(p.Arg660=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,612,362 control chromosomes in the GnomAD database, including 67,937 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6195 hom., cov: 31)
  • Exomes 𝑓: 0.28 (61742 hom.)
• Consequence: PRDM8 ENST00000415738.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.583

Genes affected

PRDM8 (HGNC:13993): (PR/SET domain 8) This gene encodes a protein that belongs to a conserved family of histone methyltransferases that predominantly act as negative regulators of transcription. The encoded protein contains an N-terminal Su(var)3-9, Enhancer-of-zeste, and Trithorax (SET) domain and a double zinc-finger domain. Knockout of this gene in mouse results in mistargeting by neurons of the dorsal telencephalon, abnormal itch-like behavior, and impaired differentiation of rod bipolar cells. In humans, the protein has been shown to interact with the phosphatase laforin and the ubiquitin ligase malin, which regulate glycogen construction in the cytoplasm. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 4-80203442-G-C is Benign according to our data. Variant chr4-80203442-G-C is described in ClinVar as [Benign]. Clinvar id is 1170071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.583 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM8	NM_001099403.2	c.1980G>C	p.Arg660=	synonymous_variant	4/4	ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4	c.1980G>C	p.Arg660=	synonymous_variant	10/10		NP_064611.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM8	ENST00000415738.3	c.1980G>C	p.Arg660=	synonymous_variant	4/4	1	NM_001099403.2	ENSP00000406998	P1
PRDM8	ENST00000339711.8	c.1980G>C	p.Arg660=	synonymous_variant	10/10	1		ENSP00000339764	P1
PRDM8	ENST00000504452.5	c.1980G>C	p.Arg660=	synonymous_variant	8/8	5		ENSP00000423985	P1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41388 AN: 151836 Hom.: 6188 Cov.: 31

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.284

GnomAD3 exomes AF: 0.321 AC: 78956 AN: 245986 Hom.: 14007 AF XY: 0.320 AC XY: 42797 AN XY: 133578

Gnomad AFR exome AF: 0.185

Gnomad AMR exome AF: 0.366

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.632

Gnomad SAS exome AF: 0.370

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.263

Gnomad OTH exome AF: 0.306

GnomAD4 exome AF: 0.281 AC: 410148 AN: 1460412 Hom.: 61742 Cov.: 45 AF XY: 0.283 AC XY: 205600 AN XY: 726324

Gnomad4 AFR exome AF: 0.190

Gnomad4 AMR exome AF: 0.365

Gnomad4 ASJ exome AF: 0.269

Gnomad4 EAS exome AF: 0.618

Gnomad4 SAS exome AF: 0.368

Gnomad4 FIN exome AF: 0.349

Gnomad4 NFE exome AF: 0.258

Gnomad4 OTH exome AF: 0.291

GnomAD4 genome AF: 0.273 AC: 41416 AN: 151950 Hom.: 6195 Cov.: 31 AF XY: 0.284 AC XY: 21079 AN XY: 74230

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.332

Gnomad4 ASJ AF: 0.276

Gnomad4 EAS AF: 0.618

Gnomad4 SAS AF: 0.383

Gnomad4 FIN AF: 0.357

Gnomad4 NFE AF: 0.262

Gnomad4 OTH AF: 0.283

Alfa AF: 0.259 Hom.: 1682

Bravo AF: 0.266

Asia WGS AF: 0.487 AC: 1688 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early-onset Lafora body disease Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 70% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 65. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.5
DANN	Benign	0.79

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: rs12780; hg19: chr4-81124596; COSMIC: COSV60202903; COSMIC: COSV60202903;