rs755316101

chr4-80203232-AGCCGCGGCTGCGGCGGCG-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP3 BP6_Very_Strong

The NM_001099403.2(PRDM8):c.1778_1795del(p.Ala593_Ala598del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,556,336 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: PRDM8 NM_001099403.2 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.29

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_001099403.2
• BP6: Variant 4-80203232-AGCCGCGGCTGCGGCGGCG-A is Benign according to our data. Variant chr4-80203232-AGCCGCGGCTGCGGCGGCG-A is described in ClinVar as [Likely_benign]. Clinvar id is 475674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM8	NM_001099403.2	c.1778_1795del	p.Ala593_Ala598del	inframe_deletion	4/4	ENST00000415738.3
PRDM8	NM_020226.4	c.1778_1795del	p.Ala593_Ala598del	inframe_deletion	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM8	ENST00000415738.3	c.1778_1795del	p.Ala593_Ala598del	inframe_deletion	4/4	1	NM_001099403.2	P1
PRDM8	ENST00000339711.8	c.1778_1795del	p.Ala593_Ala598del	inframe_deletion	10/10	1		P1
PRDM8	ENST00000504452.5	c.1778_1795del	p.Ala593_Ala598del	inframe_deletion	8/8	5		P1

Frequencies

GnomAD3 genomes AF: 0.000751 AC: 114 AN: 151748 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00823

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000339

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000936 AC: 145 AN: 154892 Hom.: 0 AF XY: 0.00106 AC XY: 90 AN XY: 85042

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000415

Gnomad FIN exome AF: 0.00783

Gnomad NFE exome AF: 0.000285

Gnomad OTH exome AF: 0.000699

GnomAD4 exome AF: 0.000367 AC: 515 AN: 1404478 Hom.: 1 AF XY: 0.000360 AC XY: 250 AN XY: 694036

Gnomad4 AFR exome AF: 0.0000631

Gnomad4 AMR exome AF: 0.000167

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000546

Gnomad4 SAS exome AF: 0.0000371

Gnomad4 FIN exome AF: 0.00591

Gnomad4 NFE exome AF: 0.000181

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000751 AC: 114 AN: 151858 Hom.: 0 Cov.: 32 AF XY: 0.00123 AC XY: 91 AN XY: 74226

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00823

Gnomad4 NFE AF: 0.000339

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000473 Hom.: 0

Bravo AF: 0.000140

ClinVar

Significance: Benign/Likely 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

Jul 09, 2023

- -

PRDM8-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 26, 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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs755316101; hg19: chr4-81124386;