4-80202309-C-A

Position:

• chr4-80202309-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001099403.2(PRDM8):​c.847C>A​(p.Leu283Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 146,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000014 (0 hom., cov: 31)
• Consequence: PRDM8 NM_001099403.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07109249).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM8	NM_001099403.2	c.847C>A	p.Leu283Ile	missense_variant	4/4	ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4	c.847C>A	p.Leu283Ile	missense_variant	10/10		NP_064611.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM8	ENST00000415738.3	c.847C>A	p.Leu283Ile	missense_variant	4/4	1	NM_001099403.2	ENSP00000406998.2
PRDM8	ENST00000339711.8	c.847C>A	p.Leu283Ile	missense_variant	10/10	1		ENSP00000339764.4
PRDM8	ENST00000515013.5	c.847C>A	p.Leu283Ile	missense_variant	10/10	1		ENSP00000425149.1
PRDM8	ENST00000504452.5	c.847C>A	p.Leu283Ile	missense_variant	8/8	5		ENSP00000423985.1

Frequencies

GnomAD3 genomes AF: 0.0000137 AC: 2 AN: 146230 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000512

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome AF: 0.0000137 AC: 2 AN: 146230 Hom.: 0 Cov.: 31 AF XY: 0.0000140 AC XY: 1 AN XY: 71392

Gnomad4 AFR AF: 0.0000512

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early-onset Lafora body disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2022

This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 283 of the PRDM8 protein (p.Leu283Ile). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 542334). This variant has not been reported in the literature in individuals affected with PRDM8-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.0063	T;.;T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.45	.;T;T;.
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.071	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;L;L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.45	N;N;N;N
REVEL	Benign	0.055
Sift	Benign	0.13	T;T;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.056	B;.;B;B
Vest4		0.13
MutPred		0.093		Gain of glycosylation at S278 (P = 0.0087);Gain of glycosylation at S278 (P = 0.0087);Gain of glycosylation at S278 (P = 0.0087);Gain of glycosylation at S278 (P = 0.0087);
MVP		0.37
ClinPred		0.085	T
GERP RS		1.7
Varity_R		0.062
gMVP		0.025

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: rs1211529205; hg19: chr4-81123463;