rs756736858

Positions:

chr4-80202330-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001099403.2(PRDM8):c.868G>A(p.Gly290Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000818 in 1,589,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

PRDM8
NM_001099403.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -1.26

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.044366807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM8	NM_001099403.2 linkuse as main transcript	c.868G>A	p.Gly290Ser	missense_variant	4/4	ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4 linkuse as main transcript	c.868G>A	p.Gly290Ser	missense_variant	10/10		NP_064611.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM8	ENST00000415738.3 linkuse as main transcript	c.868G>A	p.Gly290Ser	missense_variant	4/4	1	NM_001099403.2	ENSP00000406998	P1	Q9NQV8-1
PRDM8	ENST00000339711.8 linkuse as main transcript	c.868G>A	p.Gly290Ser	missense_variant	10/10	1		ENSP00000339764	P1	Q9NQV8-1
PRDM8	ENST00000515013.5 linkuse as main transcript	c.868G>A	p.Gly290Ser	missense_variant	10/10	1		ENSP00000425149
PRDM8	ENST00000504452.5 linkuse as main transcript	c.868G>A	p.Gly290Ser	missense_variant	8/8	5		ENSP00000423985	P1	Q9NQV8-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000373

AC:

AN:

214228

Hom.:

AF XY:

0.0000253

AC XY:

AN XY:

118714

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000218

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000109

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000834

AC:

AN:

1438204

Hom.:

Cov.:

AF XY:

0.00000419

AC XY:

AN XY:

715338

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000186

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000365

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151774

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74104

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

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

Bravo

AF:

0.0000302

ExAC

AF:

0.0000174

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2023

The c.868G>A (p.G290S) alteration is located in exon 10 (coding exon 3) of the PRDM8 gene. This alteration results from a G to A substitution at nucleotide position 868, causing the glycine (G) at amino acid position 290 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Early-onset Lafora body disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2021

This sequence change replaces glycine with serine at codon 290 of the PRDM8 protein (p.Gly290Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs756736858, ExAC 0.003%). 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: 542338). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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

Benign

0.073

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

2.7

DANN

Benign

0.97

DEOGEN2

Benign

0.0038

T;.;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.42

.;T;T;.

M_CAP

Benign

0.048

MetaRNN

Benign

0.044

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;.;N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.010

N;N;N;N

REVEL

Benign

0.061

Sift

Benign

0.062

T;T;T;T

Sift4G

Benign

0.49

T;T;T;T

Polyphen

0.037

B;.;B;B

Vest4

0.14

MutPred

0.16

Gain of solvent accessibility (P = 0.1683);Gain of solvent accessibility (P = 0.1683);Gain of solvent accessibility (P = 0.1683);Gain of solvent accessibility (P = 0.1683);

MVP

0.32

ClinPred

0.025

GERP RS

-0.48

Varity_R

0.076

gMVP

0.044

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over