rs560049733

Variant names:

• chr4-80202447-C-T
• rs560049733
• NM_001099403.2:c.985C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001099403.2(PRDM8):​c.985C>T​(p.Leu329Leu) 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, single submitter B:2
• Conservation: PhyloP100: -0.322
• 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: Benign. The variant received -7 ACMG points.

• 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 VariationId is 542340.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.322 with no splicing effect.

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.985C>T	p.Leu329Leu	synonymous	Exon 4 of 4	NP_001092873.1
	PRDM8	NM_020226.4		c.985C>T	p.Leu329Leu	synonymous	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.985C>T	p.Leu329Leu	synonymous	Exon 4 of 4	ENSP00000406998.2
	PRDM8	ENST00000339711.8	TSL:1	c.985C>T	p.Leu329Leu	synonymous	Exon 10 of 10	ENSP00000339764.4
	PRDM8	ENST00000515013.5	TSL:1	c.985C>T	p.Leu329Leu	synonymous	Exon 10 of 10	ENSP00000425149.1

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

GnomAD2 exomes AF: 0.000305 AC: 43 AN: 141148 AF XY: 0.000221

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 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

African (AFR) AF: 0.0000636 AC: 2 AN: 31440

American (AMR) AF: 0.000567 AC: 20 AN: 35278

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25058

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35762

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79276

European-Finnish (FIN) AF: 0.0000219 AC: 1 AN: 45760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5462

European-Non Finnish (NFE) AF: 0.000752 AC: 811 AN: 1078670

Other (OTH) AF: 0.000536 AC: 31 AN: 57840

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

African (AFR) AF: 0.000145 AC: 6 AN: 41430

American (AMR) AF: 0.000327 AC: 5 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000589 AC: 40 AN: 67906

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000448 Hom.: 0

Bravo AF: 0.000355

ClinVar

ClinVar submissions as Germline

Significance: Likely 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
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.9
DANN	Benign	0.90
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism

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: rs560049733; hg19: chr4-81123601;