rs28405693

Variant names:

• chr4-80203188-C-T
• rs28405693
• NM_001099403.2:c.1726C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001099403.2(PRDM8):​c.1726C>T​(p.Leu576Leu) 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.11
• Publications: 2 publications found

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]

PRDM8 Gene-Disease associations (from GenCC):

• early-onset Lafora body disease

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 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 VariationId is 475673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
PRDM8	NM_001099403.2	c.1726C>T	p.Leu576Leu	synonymous_variant	Exon 4 of 4	ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4	c.1726C>T	p.Leu576Leu	synonymous_variant	Exon 10 of 10		NP_064611.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM8	ENST00000415738.3	c.1726C>T	p.Leu576Leu	synonymous_variant	Exon 4 of 4	1	NM_001099403.2	ENSP00000406998.2
PRDM8	ENST00000339711.8	c.1726C>T	p.Leu576Leu	synonymous_variant	Exon 10 of 10	1		ENSP00000339764.4
PRDM8	ENST00000504452.5	c.1726C>T	p.Leu576Leu	synonymous_variant	Exon 8 of 8	5		ENSP00000423985.1

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

GnomAD2 exomes AF: 0.0145 AC: 2075 AN: 143544 AF XY: 0.0130

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 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

African (AFR) AF: 0.128 AC: 4053 AN: 31692

American (AMR) AF: 0.0186 AC: 682 AN: 36700

Ashkenazi Jewish (ASJ) AF: 0.000239 AC: 6 AN: 25142

East Asian (EAS) AF: 0.0486 AC: 1759 AN: 36158

South Asian (SAS) AF: 0.0106 AC: 850 AN: 80314

European-Finnish (FIN) AF: 0.0000479 AC: 2 AN: 41718

Middle Eastern (MID) AF: 0.0117 AC: 60 AN: 5128

European-Non Finnish (NFE) AF: 0.000367 AC: 398 AN: 1083462

Other (OTH) AF: 0.0125 AC: 724 AN: 58070

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

African (AFR) AF: 0.126 AC: 5244 AN: 41472

American (AMR) AF: 0.0187 AC: 286 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.0472 AC: 241 AN: 5106

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4828

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10576

Middle Eastern (MID) AF: 0.00694 AC: 2 AN: 288

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 67936

Other (OTH) AF: 0.0303 AC: 64 AN: 2114

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early-onset Lafora body disease Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.97
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28405693; hg19: chr4-81124342;