4-80202874-G-A

Position:

chr4-80202874-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001099403.2(PRDM8):c.1412G>A(p.Ser471Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,274,036 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.00058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 2 hom. )

Consequence

PRDM8
NM_001099403.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.300

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003796935).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM8	NM_001099403.2 linkuse as main transcript	c.1412G>A	p.Ser471Asn	missense_variant	4/4	ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4 linkuse as main transcript	c.1412G>A	p.Ser471Asn	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.1412G>A	p.Ser471Asn	missense_variant	4/4	1	NM_001099403.2	ENSP00000406998	P1	Q9NQV8-1
PRDM8	ENST00000339711.8 linkuse as main transcript	c.1412G>A	p.Ser471Asn	missense_variant	10/10	1		ENSP00000339764	P1	Q9NQV8-1
PRDM8	ENST00000504452.5 linkuse as main transcript	c.1412G>A	p.Ser471Asn	missense_variant	8/8	5		ENSP00000423985	P1	Q9NQV8-1

Frequencies

GnomAD3 genomes

AF:

0.000583

AC:

AN:

150984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00165

Gnomad ASJ

AF:

0.000868

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000576

Gnomad OTH

AF:

0.000962

GnomAD3 exomes

AF:

0.00633

AC:

AN:

158

Hom.:

AF XY:

0.0111

AC XY:

AN XY:

show subpopulations

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00658

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000419

AC:

470

AN:

1122944

Hom.:

Cov.:

AF XY:

0.000506

AC XY:

273

AN XY:

539100

show subpopulations

Gnomad4 AFR exome

AF:

0.0000444

Gnomad4 AMR exome

AF:

0.000625

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00429

Gnomad4 FIN exome

AF:

0.0000834

Gnomad4 NFE exome

AF:

0.000309

Gnomad4 OTH exome

AF:

0.000598

GnomAD4 genome

AF:

0.000576

AC:

AN:

151092

Hom.:

Cov.:

AF XY:

0.000569

AC XY:

AN XY:

73838

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00165

Gnomad4 ASJ

AF:

0.000868

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000576

Gnomad4 OTH

AF:

0.000952

Alfa

AF:

0.000693

Hom.:

Bravo

AF:

0.000518

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Early-onset Lafora body disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 471 of the PRDM8 protein (p.Ser471Asn). This variant is present in population databases (rs575791037, gnomAD 0.4%). 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: 542337). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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

0.099

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.011

T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.40

.;T;.

M_CAP

Benign

0.076

MetaRNN

Benign

0.0038

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.26

N;N;N

REVEL

Benign

0.0070

Sift

Benign

0.46

T;T;T

Sift4G

Benign

0.27

T;T;T

Polyphen

0.0080

B;B;B

Vest4

0.042

MVP

0.41

ClinPred

0.026

GERP RS

1.6

Varity_R

0.051

gMVP

0.099

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