4-80200201-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001099403.2(PRDM8):c.121T>G(p.Phe41Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRDM8 NM_001099403.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.10

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM8	NM_001099403.2	c.121T>G	p.Phe41Val	missense_variant	2/4	ENST00000415738.3
PRDM8	NM_020226.4	c.121T>G	p.Phe41Val	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM8	ENST00000415738.3	c.121T>G	p.Phe41Val	missense_variant	2/4	1	NM_001099403.2	P1
PRDM8	ENST00000339711.8	c.121T>G	p.Phe41Val	missense_variant	8/10	1		P1
PRDM8	ENST00000515013.5	c.121T>G	p.Phe41Val	missense_variant	8/10	1
PRDM8	ENST00000504452.5	c.121T>G	p.Phe41Val	missense_variant	6/8	5		P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Invitae

Dec 11, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 41 of the PRDM8 protein (p.Phe41Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRDM8-related conditions. ClinVar contains an entry for this variant (Variation ID: 1389691). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRDM8 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.8	M;.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-4.3	D;D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.78	P;.;P;P
Vest4		0.93
MutPred		0.72		Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);
MVP		0.98
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.68
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-81121355;