rs200777615

Positions:

• chr4-80201399-G-A
• chr4-80201399-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001099403.2(PRDM8):​c.329G>A​(p.Gly110Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRDM8 NM_001099403.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM8	NM_001099403.2	c.329G>A	p.Gly110Glu	missense_variant	3/4	ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4	c.329G>A	p.Gly110Glu	missense_variant	9/10		NP_064611.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM8	ENST00000415738.3	c.329G>A	p.Gly110Glu	missense_variant	3/4	1	NM_001099403.2	ENSP00000406998.2
PRDM8	ENST00000339711.8	c.329G>A	p.Gly110Glu	missense_variant	9/10	1		ENSP00000339764.4
PRDM8	ENST00000515013.5	c.329G>A	p.Gly110Glu	missense_variant	9/10	1		ENSP00000425149.1
PRDM8	ENST00000504452.5	c.329G>A	p.Gly110Glu	missense_variant	7/8	5		ENSP00000423985.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249586 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135408

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;T;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	.;T;D;.
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.1	M;.;M;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.1	D;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.88
MutPred		0.67		Loss of MoRF binding (P = 0.0362);Loss of MoRF binding (P = 0.0362);Loss of MoRF binding (P = 0.0362);Loss of MoRF binding (P = 0.0362);
MVP		1.0
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.81
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 28

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200777615; hg19: chr4-81122553; COSMIC: COSV60203625; COSMIC: COSV60203625;