chr4-80203232-AGCCGCGGCTGCGGCGGCG-A

Variant names:

• chr4-80203232-AGCCGCGGCTGCGGCGGCG-A
• rs755316101
• NM_001099403.2:c.1778_1795delCTGCGGCGGCGGCCGCGG

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP3 BP6_Moderate

The NM_001099403.2(PRDM8):​c.1778_1795delCTGCGGCGGCGGCCGCGG​(p.Ala593_Ala598del) variant causes a disruptive 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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: PRDM8 NM_001099403.2 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 3.29
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• 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 Benign. ClinVar VariationId is 475674.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099403.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM8	NM_001099403.2	MANE Select	c.1778_1795delCTGCGGCGGCGGCCGCGG	p.Ala593_Ala598del	disruptive_inframe_deletion	Exon 4 of 4	NP_001092873.1
	PRDM8	NM_020226.4		c.1778_1795delCTGCGGCGGCGGCCGCGG	p.Ala593_Ala598del	disruptive_inframe_deletion	Exon 10 of 10	NP_064611.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM8	ENST00000415738.3	TSL:1 MANE Select	c.1778_1795delCTGCGGCGGCGGCCGCGG	p.Ala593_Ala598del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000406998.2
	PRDM8	ENST00000339711.8	TSL:1	c.1778_1795delCTGCGGCGGCGGCCGCGG	p.Ala593_Ala598del	disruptive_inframe_deletion	Exon 10 of 10	ENSP00000339764.4
	PRDM8	ENST00000504452.5	TSL:5	c.1778_1795delCTGCGGCGGCGGCCGCGG	p.Ala593_Ala598del	disruptive_inframe_deletion	Exon 8 of 8	ENSP00000423985.1

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

GnomAD2 exomes AF: 0.000936 AC: 145 AN: 154892 AF XY: 0.00106

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 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

African (AFR) AF: 0.0000631 AC: 2 AN: 31676

American (AMR) AF: 0.000167 AC: 6 AN: 35846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24922

East Asian (EAS) AF: 0.0000546 AC: 2 AN: 36600

South Asian (SAS) AF: 0.0000371 AC: 3 AN: 80776

European-Finnish (FIN) AF: 0.00591 AC: 280 AN: 47360

Middle Eastern (MID) AF: 0.000206 AC: 1 AN: 4852

European-Non Finnish (NFE) AF: 0.000181 AC: 196 AN: 1084436

Other (OTH) AF: 0.000431 AC: 25 AN: 58010

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

African (AFR) AF: 0.0000724 AC: 3 AN: 41446

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5088

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00823 AC: 87 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000339 AC: 23 AN: 67896

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000473 Hom.: 0

Bravo AF: 0.000140

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Early-onset Lafora body disease (1)
-	-	1	PRDM8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=173/27	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs755316101; hg19: chr4-81124386;