rs758969495

Positions:

• chr4-80203417-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000415738.3(PRDM8):​c.1955A>G​(p.Tyr652Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Y652Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PRDM8 ENST00000415738.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM8	NM_001099403.2	c.1955A>G	p.Tyr652Cys	missense_variant	4/4	ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4	c.1955A>G	p.Tyr652Cys	missense_variant	10/10		NP_064611.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM8	ENST00000415738.3	c.1955A>G	p.Tyr652Cys	missense_variant	4/4	1	NM_001099403.2	ENSP00000406998	P1
PRDM8	ENST00000339711.8	c.1955A>G	p.Tyr652Cys	missense_variant	10/10	1		ENSP00000339764	P1
PRDM8	ENST00000504452.5	c.1955A>G	p.Tyr652Cys	missense_variant	8/8	5		ENSP00000423985	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000805 AC: 2 AN: 248310 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461580 Hom.: 0 Cov.: 36 AF XY: 0.00000688 AC XY: 5 AN XY: 727032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Feb 14, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PRDM8-related disease. This variant is present in population databases (rs758969495, ExAC 0.003%). This sequence change replaces tyrosine with cysteine at codon 652 of the PRDM8 protein (p.Tyr652Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.0050	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	.;D;.
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.98	L;L;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.026	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.60
MutPred		0.36		Gain of glycosylation at Y652 (P = 0.0029);Gain of glycosylation at Y652 (P = 0.0029);Gain of glycosylation at Y652 (P = 0.0029);
MVP		0.71
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.32
gMVP		0.55

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: rs758969495; hg19: chr4-81124571;