rs575791037

Positions:

• chr4-80202874-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001099403.2(PRDM8):​c.1412G>A​(p.Ser471Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,274,036 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (2 hom.)
• Consequence: PRDM8 NM_001099403.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.300

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003796935).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM8	NM_001099403.2	c.1412G>A	p.Ser471Asn	missense_variant	4/4	ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4	c.1412G>A	p.Ser471Asn	missense_variant	10/10		NP_064611.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM8	ENST00000415738.3	c.1412G>A	p.Ser471Asn	missense_variant	4/4	1	NM_001099403.2	ENSP00000406998	P1
PRDM8	ENST00000339711.8	c.1412G>A	p.Ser471Asn	missense_variant	10/10	1		ENSP00000339764	P1
PRDM8	ENST00000504452.5	c.1412G>A	p.Ser471Asn	missense_variant	8/8	5		ENSP00000423985	P1

Frequencies

GnomAD3 genomes AF: 0.000583 AC: 88 AN: 150984 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00165

Gnomad ASJ AF: 0.000868

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000576

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.00633 AC: 1 AN: 158 Hom.: 0 AF XY: 0.0111 AC XY: 1 AN XY: 90

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00658

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000419 AC: 470 AN: 1122944 Hom.: 2 Cov.: 36 AF XY: 0.000506 AC XY: 273 AN XY: 539100

Gnomad4 AFR exome AF: 0.0000444

Gnomad4 AMR exome AF: 0.000625

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00429

Gnomad4 FIN exome AF: 0.0000834

Gnomad4 NFE exome AF: 0.000309

Gnomad4 OTH exome AF: 0.000598

GnomAD4 genome AF: 0.000576 AC: 87 AN: 151092 Hom.: 0 Cov.: 32 AF XY: 0.000569 AC XY: 42 AN XY: 73838

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00165

Gnomad4 ASJ AF: 0.000868

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000576

Gnomad4 OTH AF: 0.000952

Alfa AF: 0.000693 Hom.: 0

Bravo AF: 0.000518

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early-onset Lafora body disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 471 of the PRDM8 protein (p.Ser471Asn). This variant is present in population databases (rs575791037, gnomAD 0.4%). 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: 542337). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	0.099
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.011	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.40	.;T;.
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.0038	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.26	N;N;N
REVEL	Benign	0.0070
Sift	Benign	0.46	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0080	B;B;B
Vest4		0.042
MVP		0.41
ClinPred		0.026	T
GERP RS		1.6
Varity_R		0.051
gMVP		0.099

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

Other links and lift over

dbSNP: rs575791037; hg19: chr4-81124028;