NM_001099403.2:c.1390C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001099403.2(PRDM8):​c.1390C>T​(p.Pro464Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000743 in 1,233,840 control chromosomes in the GnomAD database, including 10 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 (★). Synonymous variant affecting the same amino acid position (i.e. P464P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0037 ( 5 hom., cov: 32)
Exomes 𝑓: 0.00033 ( 5 hom. )

Consequence

PRDM8
NM_001099403.2 missense

Scores

1
17

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0550

Publications

1 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.00395).
BP6
Variant 4-80202852-C-T is Benign according to our data. Variant chr4-80202852-C-T is described in CliVar as Benign. Clinvar id is 475668.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-80202852-C-T is described in CliVar as Benign. Clinvar id is 475668.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-80202852-C-T is described in CliVar as Benign. Clinvar id is 475668.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-80202852-C-T is described in CliVar as Benign. Clinvar id is 475668.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-80202852-C-T is described in CliVar as Benign. Clinvar id is 475668.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-80202852-C-T is described in CliVar as Benign. Clinvar id is 475668.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-80202852-C-T is described in CliVar as Benign. Clinvar id is 475668.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-80202852-C-T is described in CliVar as Benign. Clinvar id is 475668.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-80202852-C-T is described in CliVar as Benign. Clinvar id is 475668.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-80202852-C-T is described in CliVar as Benign. Clinvar id is 475668.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-80202852-C-T is described in CliVar as Benign. Clinvar id is 475668.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRDM8NM_001099403.2 linkc.1390C>T p.Pro464Ser missense_variant Exon 4 of 4 ENST00000415738.3 NP_001092873.1 Q9NQV8-1A0A024RDC4Q05CA1
PRDM8NM_020226.4 linkc.1390C>T p.Pro464Ser missense_variant Exon 10 of 10 NP_064611.3 Q9NQV8-1A0A024RDC4Q05CA1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRDM8ENST00000415738.3 linkc.1390C>T p.Pro464Ser missense_variant Exon 4 of 4 1 NM_001099403.2 ENSP00000406998.2 Q9NQV8-1
PRDM8ENST00000339711.8 linkc.1390C>T p.Pro464Ser missense_variant Exon 10 of 10 1 ENSP00000339764.4 Q9NQV8-1
PRDM8ENST00000504452.5 linkc.1390C>T p.Pro464Ser missense_variant Exon 8 of 8 5 ENSP00000423985.1 Q9NQV8-1
PRDM8ENST00000515013.5 linkc.*107C>T downstream_gene_variant 1 ENSP00000425149.1 E9PEH0

Frequencies

GnomAD3 genomes
AF:
0.00370
AC:
559
AN:
150932
Hom.:
5
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0130
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000792
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:
0.0000739
Gnomad OTH
AF:
0.00338
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
106
AF XY:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000331
AC:
358
AN:
1082800
Hom.:
5
Cov.:
36
AF XY:
0.000317
AC XY:
163
AN XY:
514854
show subpopulations
African (AFR)
AF:
0.0145
AC:
320
AN:
22098
American (AMR)
AF:
0.000390
AC:
3
AN:
7684
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
13386
East Asian (EAS)
AF:
0.00
AC:
0
AN:
24494
South Asian (SAS)
AF:
0.0000459
AC:
1
AN:
21770
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
21636
Middle Eastern (MID)
AF:
0.000349
AC:
1
AN:
2868
European-Non Finnish (NFE)
AF:
0.00000216
AC:
2
AN:
925784
Other (OTH)
AF:
0.000720
AC:
31
AN:
43080
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.509
Heterozygous variant carriers
0
23
46
70
93
116
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
20
40
60
80
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:
0.00370
AC:
559
AN:
151040
Hom.:
5
Cov.:
32
AF XY:
0.00374
AC XY:
276
AN XY:
73804
show subpopulations
African (AFR)
AF:
0.0129
AC:
535
AN:
41412
American (AMR)
AF:
0.000791
AC:
12
AN:
15172
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3456
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5116
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10148
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.0000739
AC:
5
AN:
67616
Other (OTH)
AF:
0.00334
AC:
7
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
28
56
84
112
140
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<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:
0.00203
Hom.:
1
Asia WGS
AF:
0.000607
AC:
2
AN:
3308

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Early-onset Lafora body disease Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.59
T
BayesDel_noAF
Benign
-0.61
CADD
Benign
16
DANN
Benign
0.97
DEOGEN2
Benign
0.025
T;T;T
Eigen
Benign
-0.56
Eigen_PC
Benign
-0.44
FATHMM_MKL
Benign
0.51
D
LIST_S2
Benign
0.59
.;T;.
MetaRNN
Benign
0.0040
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.20
N;N;N
PhyloP100
0.055
PrimateAI
Pathogenic
0.91
D
PROVEAN
Benign
-1.3
N;N;N
REVEL
Benign
0.022
Sift
Benign
0.16
T;T;T
Sift4G
Benign
0.34
T;T;T
Polyphen
0.0
B;B;B
Vest4
0.022
MVP
0.60
ClinPred
0.080
T
GERP RS
1.8
Varity_R
0.036
gMVP
0.21
Mutation Taster
=98/2
polymorphism

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

Other links and lift over

dbSNP: rs201251555; hg19: chr4-81124006; API