rs544862921

Variant names:

• chr4-80202909-G-A
• rs544862921
• NM_001099403.2:c.1447G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-80202909-G-A
• chr4-80202909-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001099403.2(PRDM8):​c.1447G>A​(p.Ala483Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000842 in 1,187,522 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A483S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: PRDM8 NM_001099403.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.387
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08508742).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM8	NM_001099403.2	c.1447G>A	p.Ala483Thr	missense_variant	Exon 4 of 4	ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4	c.1447G>A	p.Ala483Thr	missense_variant	Exon 10 of 10		NP_064611.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM8	ENST00000415738.3	c.1447G>A	p.Ala483Thr	missense_variant	Exon 4 of 4	1	NM_001099403.2	ENSP00000406998.2
PRDM8	ENST00000339711.8	c.1447G>A	p.Ala483Thr	missense_variant	Exon 10 of 10	1		ENSP00000339764.4
PRDM8	ENST00000504452.5	c.1447G>A	p.Ala483Thr	missense_variant	Exon 8 of 8	5		ENSP00000423985.1
PRDM8	ENST00000515013.5	c.*164G>A		downstream_gene_variant		1		ENSP00000425149.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.42e-7 AC: 1 AN: 1187522 Hom.: 0 Cov.: 36 AF XY: 0.00000173 AC XY: 1 AN XY: 577146

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23592

American (AMR) AF: 0.00 AC: 0 AN: 9128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15964

East Asian (EAS) AF: 0.00 AC: 0 AN: 27030

South Asian (SAS) AF: 0.0000226 AC: 1 AN: 44240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 988340

Other (OTH) AF: 0.00 AC: 0 AN: 48552

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early-onset Lafora body disease Uncertain:1

May 03, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with threonine at codon 483 of the PRDM8 protein (p.Ala483Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with PRDM8-related conditions. 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	0.074
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.0092	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.49	.;T;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.085	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;N
PhyloP100		-0.39
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.060	N;N;N
REVEL	Benign	0.048
Sift	Benign	0.087	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.037	B;B;B
Vest4		0.15
MutPred		0.15		Gain of glycosylation at T478 (P = 0.0568);Gain of glycosylation at T478 (P = 0.0568);Gain of glycosylation at T478 (P = 0.0568);
MVP		0.51
ClinPred		0.069	T
GERP RS		1.9
Varity_R		0.050
gMVP		0.22
Mutation Taster		=97/3	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

Other links and lift over

dbSNP: rs544862921; hg19: chr4-81124063;