rs575791037

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/22 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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

early-onset Lafora body disease
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

PRDM8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PRDM8	NM_001099403.2 link	c.1412G>A	p.Ser471Asn	missense_variant	Exon 4 of 4	ENST00000415738.3	NP_001092873.1	Q9NQV8-1A0A024RDC4Q05CA1
PRDM8	NM_020226.4 link	c.1412G>A	p.Ser471Asn	missense_variant	Exon 10 of 10		NP_064611.3	Q9NQV8-1A0A024RDC4Q05CA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRDM8	ENST00000415738.3 link	c.1412G>A	p.Ser471Asn	missense_variant	Exon 4 of 4	1	NM_001099403.2	ENSP00000406998.2	Q9NQV8-1
PRDM8	ENST00000339711.8 link	c.1412G>A	p.Ser471Asn	missense_variant	Exon 10 of 10	1		ENSP00000339764.4	Q9NQV8-1
PRDM8	ENST00000504452.5 link	c.1412G>A	p.Ser471Asn	missense_variant	Exon 8 of 8	5		ENSP00000423985.1	Q9NQV8-1
PRDM8	ENST00000515013.5 link	c.*129G>A		downstream_gene_variant		1		ENSP00000425149.1	E9PEH0

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

GnomAD2 exomes

AF:

0.00633

AC:

AN:

158

AF XY:

0.0111

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

African (AFR)

AF:

0.0000444

AC:

AN:

22540

American (AMR)

AF:

0.000625

AC:

AN:

8000

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

14236

East Asian (EAS)

AF:

0.00

AC:

AN:

25368

South Asian (SAS)

AF:

0.00429

AC:

129

AN:

30090

European-Finnish (FIN)

AF:

0.0000834

AC:

AN:

23982

Middle Eastern (MID)

AF:

0.00200

AC:

AN:

2996

European-Non Finnish (NFE)

AF:

0.000309

AC:

294

AN:

950584

Other (OTH)

AF:

0.000598

AC:

AN:

45148

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

108

135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000576

AC:

AN:

151092

Hom.:

Cov.:

AF XY:

0.000569

AC XY:

AN XY:

73838

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41412

American (AMR)

AF:

0.00165

AC:

AN:

15172

Ashkenazi Jewish (ASJ)

AF:

0.000868

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.00269

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000576

AC:

AN:

67658

Other (OTH)

AF:

0.000952

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Jan 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

0.30

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

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over