4-80200244-T-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001099403.2(PRDM8):c.164T>A(p.Ile55Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000713 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I55V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

PRDM8
NM_001099403.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.08

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM8	NM_001099403.2 link	c.164T>A	p.Ile55Lys	missense_variant	Exon 2 of 4	ENST00000415738.3	NP_001092873.1	Q9NQV8-1A0A024RDC4Q05CA1
PRDM8	NM_020226.4 link	c.164T>A	p.Ile55Lys	missense_variant	Exon 8 of 10		NP_064611.3	Q9NQV8-1A0A024RDC4Q05CA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRDM8	ENST00000415738.3 link	c.164T>A	p.Ile55Lys	missense_variant	Exon 2 of 4	1	NM_001099403.2	ENSP00000406998.2	Q9NQV8-1
PRDM8	ENST00000339711.8 link	c.164T>A	p.Ile55Lys	missense_variant	Exon 8 of 10	1		ENSP00000339764.4	Q9NQV8-1
PRDM8	ENST00000515013.5 link	c.164T>A	p.Ile55Lys	missense_variant	Exon 8 of 10	1		ENSP00000425149.1	E9PEH0
PRDM8	ENST00000504452.5 link	c.164T>A	p.Ile55Lys	missense_variant	Exon 6 of 8	5		ENSP00000423985.1	Q9NQV8-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000240

AC:

AN:

249578

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000773

AC:

113

AN:

1461822

Hom.:

Cov.:

AF XY:

0.0000756

AC XY:

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000917

AC:

102

AN:

1111954

Other (OTH)

AF:

0.000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

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

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 55 of the PRDM8 protein (p.Ile55Lys). This variant is present in population databases (rs762557383, gnomAD 0.004%). 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: 565874). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PRDM8 protein function with a negative predictive value of 80%. 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

1.0

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.17

T;.;T;T

Eigen

Benign

0.044

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

.;D;D;.

M_CAP

Benign

0.042

MetaRNN

Uncertain

0.48

T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.9

L;.;L;L

PhyloP100

6.1

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.5

D;D;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.021

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

0.049

B;.;B;B

Vest4

0.70

MutPred

0.55

Gain of ubiquitination at I55 (P = 0.0117);Gain of ubiquitination at I55 (P = 0.0117);Gain of ubiquitination at I55 (P = 0.0117);Gain of ubiquitination at I55 (P = 0.0117);

MVP

0.92

ClinPred

0.74

GERP RS

4.2

Varity_R

0.35

gMVP

0.76

Mutation Taster

=50/50

(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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4-80200244-T-A

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