rs28405693

chr4-80203188-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001099403.2(PRDM8):c.1726C>T(p.Leu576=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00934 in 1,550,366 control chromosomes in the GnomAD database, including 697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.039 (347 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (350 hom.)
• Consequence: PRDM8 NM_001099403.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.11

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 4-80203188-C-T is Benign according to our data. Variant chr4-80203188-C-T is described in ClinVar as [Benign]. Clinvar id is 475673.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM8	NM_001099403.2	c.1726C>T	p.Leu576=	synonymous_variant	4/4	ENST00000415738.3
PRDM8	NM_020226.4	c.1726C>T	p.Leu576=	synonymous_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM8	ENST00000415738.3	c.1726C>T	p.Leu576=	synonymous_variant	4/4	1	NM_001099403.2	P1
PRDM8	ENST00000339711.8	c.1726C>T	p.Leu576=	synonymous_variant	10/10	1		P1
PRDM8	ENST00000504452.5	c.1726C>T	p.Leu576=	synonymous_variant	8/8	5		P1

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5911 AN: 151876 Hom.: 344 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0472

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0145 AC: 2075 AN: 143544 Hom.: 82 AF XY: 0.0130 AC XY: 1022 AN XY: 78896

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.0163

Gnomad ASJ exome AF: 0.000123

Gnomad EAS exome AF: 0.0428

Gnomad SAS exome AF: 0.0109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000569

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.00610 AC: 8534 AN: 1398384 Hom.: 350 Cov.: 36 AF XY: 0.00580 AC XY: 4009 AN XY: 690996

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.0186

Gnomad4 ASJ exome AF: 0.000239

Gnomad4 EAS exome AF: 0.0486

Gnomad4 SAS exome AF: 0.0106

Gnomad4 FIN exome AF: 0.0000479

Gnomad4 NFE exome AF: 0.000367

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.0391 AC: 5939 AN: 151982 Hom.: 347 Cov.: 32 AF XY: 0.0380 AC XY: 2822 AN XY: 74294

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.0187

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0472

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0176 Hom.: 22

Bravo AF: 0.0445

Asia WGS AF: 0.0360 AC: 125 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early-onset Lafora body disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	11
Dann	Benign	0.97

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: rs28405693; hg19: chr4-81124342;