4-80203113-G-A

Variant names:

• chr4-80203113-G-A
• rs762888947
• NM_001099403.2:c.1651G>A
• PRDM8 p.Gly551Arg

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001099403.2(PRDM8):​c.1651G>A​(p.Gly551Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000988 in 1,417,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: PRDM8 NM_001099403.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.93
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041518837).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099403.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM8	NM_001099403.2	MANE Select	c.1651G>A	p.Gly551Arg	missense	Exon 4 of 4	NP_001092873.1	Q9NQV8-1
	PRDM8	NM_020226.4		c.1651G>A	p.Gly551Arg	missense	Exon 10 of 10	NP_064611.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM8	ENST00000415738.3	TSL:1 MANE Select	c.1651G>A	p.Gly551Arg	missense	Exon 4 of 4	ENSP00000406998.2	Q9NQV8-1
	PRDM8	ENST00000339711.8	TSL:1	c.1651G>A	p.Gly551Arg	missense	Exon 10 of 10	ENSP00000339764.4	Q9NQV8-1
	PRDM8	ENST00000952376.1		c.1654G>A	p.Gly552Arg	missense	Exon 4 of 4	ENSP00000622435.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000755 AC: 13 AN: 172170 AF XY: 0.0000727

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000951

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000988 AC: 14 AN: 1417298 Hom.: 0 Cov.: 36 AF XY: 0.00000853 AC XY: 6 AN XY: 703264

African (AFR) AF: 0.00 AC: 0 AN: 31650

American (AMR) AF: 0.00 AC: 0 AN: 41364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25380

East Asian (EAS) AF: 0.000374 AC: 14 AN: 37404

South Asian (SAS) AF: 0.00 AC: 0 AN: 82446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5420

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098246

Other (OTH) AF: 0.00 AC: 0 AN: 58954

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Early-onset Lafora body disease (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.056
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.015	D
Varity_R		0.14
gMVP		0.50
Mutation Taster		=73/27	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs762888947;

hg19: chr4-81124267;