4-80202909-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001099403.2(PRDM8):c.1447G>T(p.Ala483Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000937 in 1,338,846 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A483T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0047 ( 8 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 4 hom. )

Consequence

PRDM8
NM_001099403.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.387

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015520751).

BP6

Variant 4-80202909-G-T is Benign according to our data. Variant chr4-80202909-G-T is described in ClinVar as Benign. ClinVar VariationId is 475669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00471 (713/151318) while in subpopulation AFR AF = 0.0161 (667/41448). AF 95% confidence interval is 0.0151. There are 8 homozygotes in GnomAd4. There are 336 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM8	NM_001099403.2 link	c.1447G>T	p.Ala483Ser	missense_variant	Exon 4 of 4	ENST00000415738.3	NP_001092873.1	Q9NQV8-1A0A024RDC4Q05CA1
PRDM8	NM_020226.4 link	c.1447G>T	p.Ala483Ser	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.1447G>T	p.Ala483Ser	missense_variant	Exon 4 of 4	1	NM_001099403.2	ENSP00000406998.2	Q9NQV8-1
PRDM8	ENST00000339711.8 link	c.1447G>T	p.Ala483Ser	missense_variant	Exon 10 of 10	1		ENSP00000339764.4	Q9NQV8-1
PRDM8	ENST00000504452.5 link	c.1447G>T	p.Ala483Ser	missense_variant	Exon 8 of 8	5		ENSP00000423985.1	Q9NQV8-1
PRDM8	ENST00000515013.5 link	c.*164G>T		downstream_gene_variant		1		ENSP00000425149.1	E9PEH0

Frequencies

GnomAD3 genomes

AF:

0.00468

AC:

708

AN:

151210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0160

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00191

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0000885

Gnomad OTH

AF:

0.00432

GnomAD2 exomes

AF:

0.00212

AC:

AN:

4236

AF XY:

0.00140

show subpopulations

Gnomad AFR exome

AF:

0.0473

Gnomad AMR exome

AF:

0.00518

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000456

AC:

541

AN:

1187528

Hom.:

Cov.:

AF XY:

0.000435

AC XY:

251

AN XY:

577150

show subpopulations

African (AFR)

AF:

0.0163

AC:

384

AN:

23592

American (AMR)

AF:

0.00164

AC:

AN:

9128

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15964

East Asian (EAS)

AF:

0.00

AC:

AN:

27030

South Asian (SAS)

AF:

0.000136

AC:

AN:

44240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27368

Middle Eastern (MID)

AF:

0.00302

AC:

AN:

3310

European-Non Finnish (NFE)

AF:

0.0000587

AC:

AN:

988342

Other (OTH)

AF:

0.00140

AC:

AN:

48554

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

123

154

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:

0.00471

AC:

713

AN:

151318

Hom.:

Cov.:

AF XY:

0.00454

AC XY:

336

AN XY:

73966

show subpopulations

African (AFR)

AF:

0.0161

AC:

667

AN:

41448

American (AMR)

AF:

0.00191

AC:

AN:

15178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10190

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000885

AC:

AN:

67762

Other (OTH)

AF:

0.00427

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

110

146

183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00319

Hom.:

ExAC

AF:

0.000321

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Early-onset Lafora body disease

Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

1.9

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.0063

T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.40

.;T;.

MetaRNN

Benign

0.0016

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;N

PhyloP100

-0.39

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.11

N;N;N

REVEL

Benign

0.022

Sift

Benign

0.52

T;T;T

Sift4G

Benign

0.38

T;T;T

Polyphen

0.0020

B;B;B

Vest4

0.11

MVP

0.43

ClinPred

0.0048

GERP RS

1.9

Varity_R

0.060

gMVP

0.20

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