rs560049733

chr4-80202447-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001099403.2(PRDM8):c.985C>T(p.Leu329=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000596 in 1,546,454 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L329L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (1 hom.)
• Consequence: PRDM8 NM_001099403.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.322

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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-80202447-C-T is Benign according to our data. Variant chr4-80202447-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 542340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.322 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM8	NM_001099403.2	c.985C>T	p.Leu329=	synonymous_variant	4/4	ENST00000415738.3
PRDM8	NM_020226.4	c.985C>T	p.Leu329=	synonymous_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM8	ENST00000415738.3	c.985C>T	p.Leu329=	synonymous_variant	4/4	1	NM_001099403.2	P1
PRDM8	ENST00000339711.8	c.985C>T	p.Leu329=	synonymous_variant	10/10	1		P1
PRDM8	ENST00000515013.5	c.985C>T	p.Leu329=	synonymous_variant	10/10	1
PRDM8	ENST00000504452.5	c.985C>T	p.Leu329=	synonymous_variant	8/8	5		P1

Frequencies

GnomAD3 genomes AF: 0.000356 AC: 54 AN: 151790 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000589

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000305 AC: 43 AN: 141148 Hom.: 0 AF XY: 0.000221 AC XY: 17 AN XY: 76750

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.000497

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000533

Gnomad OTH exome AF: 0.000242

GnomAD4 exome AF: 0.000622 AC: 868 AN: 1394546 Hom.: 1 Cov.: 37 AF XY: 0.000577 AC XY: 397 AN XY: 688068

Gnomad4 AFR exome AF: 0.0000636

Gnomad4 AMR exome AF: 0.000567

Gnomad4 ASJ exome AF: 0.0000399

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.0000219

Gnomad4 NFE exome AF: 0.000752

Gnomad4 OTH exome AF: 0.000536

GnomAD4 genome AF: 0.000355 AC: 54 AN: 151908 Hom.: 0 Cov.: 32 AF XY: 0.000337 AC XY: 25 AN XY: 74264

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000589

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000448 Hom.: 0

Bravo AF: 0.000355

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early-onset Lafora body disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

PRDM8-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2019

This variant is classified as likely 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	-0.84
Cadd	Benign	1.9
Dann	Benign	0.90

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: rs560049733; hg19: chr4-81123601;