4-80202183-C-T

Position:

chr4-80202183-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001099403.2(PRDM8):c.721C>T(p.Pro241Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,611,844 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00054 ( 1 hom., cov: 31)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

PRDM8
NM_001099403.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.17

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.023380935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM8	NM_001099403.2 link	c.721C>T	p.Pro241Ser	missense_variant	4/4	ENST00000415738.3	NP_001092873.1	Q9NQV8-1A0A024RDC4Q05CA1
PRDM8	NM_020226.4 link	c.721C>T	p.Pro241Ser	missense_variant	10/10		NP_064611.3	Q9NQV8-1A0A024RDC4Q05CA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PRDM8	ENST00000415738.3 link	c.721C>T	p.Pro241Ser	missense_variant	4/4	1	NM_001099403.2	ENSP00000406998.2	Q9NQV8-1
PRDM8	ENST00000339711.8 link	c.721C>T	p.Pro241Ser	missense_variant	10/10	1		ENSP00000339764.4	Q9NQV8-1
PRDM8	ENST00000515013.5 link	c.721C>T	p.Pro241Ser	missense_variant	10/10	1		ENSP00000425149.1	E9PEH0
PRDM8	ENST00000504452.5 link	c.721C>T	p.Pro241Ser	missense_variant	8/8	5		ENSP00000423985.1	Q9NQV8-1

Frequencies

GnomAD3 genomes

AF:

0.000542

AC:

AN:

151306

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00182

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

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:

0.0000147

Gnomad OTH

AF:

0.000961

GnomAD3 exomes

AF:

0.000158

AC:

AN:

240268

Hom.:

AF XY:

0.0000986

AC XY:

AN XY:

131816

show subpopulations

Gnomad AFR exome

AF:

0.00205

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000941

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000630

AC:

AN:

1460418

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

726532

show subpopulations

Gnomad4 AFR exome

AF:

0.00191

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000542

AC:

AN:

151426

Hom.:

Cov.:

AF XY:

0.000500

AC XY:

AN XY:

73982

show subpopulations

Gnomad4 AFR

AF:

0.00182

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000951

Alfa

AF:

0.000172

Hom.:

ESP6500AA

AF:

0.00171

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000109

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.721C>T (p.P241S) alteration is located in exon 10 (coding exon 3) of the PRDM8 gene. This alteration results from a C to T substitution at nucleotide position 721, causing the proline (P) at amino acid position 241 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Early-onset Lafora body disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 241 of the PRDM8 protein (p.Pro241Ser). This variant is present in population databases (rs201806195, gnomAD 0.2%). 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: 542335). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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

0.073

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.028

T;.;T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.63

.;T;T;.

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.023

T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.7

L;.;L;L

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.6

D;D;D;D

REVEL

Benign

0.11

Sift

Uncertain

0.0050

D;T;D;D

Sift4G

Benign

0.21

T;T;T;T

Polyphen

0.44

B;.;B;B

Vest4

0.086

MVP

0.75

ClinPred

0.047

GERP RS

4.8

Varity_R

0.14

gMVP

0.18

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