rs150632206

chr4-80203145-C-T

Variant summary

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

The NM_001099403.2(PRDM8):c.1683C>T(p.Ser561=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,554,360 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (66 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (92 hom.)
• Consequence: PRDM8 NM_001099403.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.708

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=-0.64).
• BP6: Variant 4-80203145-C-T is Benign according to our data. Variant chr4-80203145-C-T is described in ClinVar as [Benign]. Clinvar id is 475672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.708 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM8	NM_001099403.2	c.1683C>T	p.Ser561=	synonymous_variant	4/4	ENST00000415738.3
PRDM8	NM_020226.4	c.1683C>T	p.Ser561=	synonymous_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM8	ENST00000415738.3	c.1683C>T	p.Ser561=	synonymous_variant	4/4	1	NM_001099403.2	P1
PRDM8	ENST00000339711.8	c.1683C>T	p.Ser561=	synonymous_variant	10/10	1		P1
PRDM8	ENST00000504452.5	c.1683C>T	p.Ser561=	synonymous_variant	8/8	5		P1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2696 AN: 151656 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.0619

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00675

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.0000737

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.00375 AC: 559 AN: 149068 Hom.: 21 AF XY: 0.00286 AC XY: 237 AN XY: 82890

Gnomad AFR exome AF: 0.0739

Gnomad AMR exome AF: 0.00285

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000708

GnomAD4 exome AF: 0.00181 AC: 2533 AN: 1402594 Hom.: 92 Cov.: 36 AF XY: 0.00155 AC XY: 1078 AN XY: 694462

Gnomad4 AFR exome AF: 0.0650

Gnomad4 AMR exome AF: 0.00348

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000247

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000505

Gnomad4 OTH exome AF: 0.00450

GnomAD4 genome AF: 0.0178 AC: 2702 AN: 151766 Hom.: 66 Cov.: 32 AF XY: 0.0171 AC XY: 1272 AN XY: 74204

Gnomad4 AFR AF: 0.0619

Gnomad4 AMR AF: 0.00674

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000737

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00920 Hom.: 7

Bravo AF: 0.0199

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early-onset Lafora body disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

PRDM8-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	7.7
Dann	Benign	0.89

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: rs150632206; hg19: chr4-81124299;