4-80202309-C-T

Position:

• chr4-80202309-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001099403.2(PRDM8):​c.847C>T​(p.Leu283Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRDM8 NM_001099403.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.24

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12173352).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM8	NM_001099403.2	c.847C>T	p.Leu283Phe	missense_variant	4/4	ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4	c.847C>T	p.Leu283Phe	missense_variant	10/10		NP_064611.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM8	ENST00000415738.3	c.847C>T	p.Leu283Phe	missense_variant	4/4	1	NM_001099403.2	ENSP00000406998.2
PRDM8	ENST00000339711.8	c.847C>T	p.Leu283Phe	missense_variant	10/10	1		ENSP00000339764.4
PRDM8	ENST00000515013.5	c.847C>T	p.Leu283Phe	missense_variant	10/10	1		ENSP00000425149.1
PRDM8	ENST00000504452.5	c.847C>T	p.Leu283Phe	missense_variant	8/8	5		ENSP00000423985.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000859 AC: 2 AN: 232914 Hom.: 0 AF XY: 0.00000776 AC XY: 1 AN XY: 128798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000115

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T;.;T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.49	.;T;T;.
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L;.;L;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.73	N;N;N;N
REVEL	Benign	0.076
Sift	Benign	0.050	D;D;D;D
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.74	P;.;P;P
Vest4		0.049
MutPred		0.12		Gain of glycosylation at S278 (P = 0.0087);Gain of glycosylation at S278 (P = 0.0087);Gain of glycosylation at S278 (P = 0.0087);Gain of glycosylation at S278 (P = 0.0087);
MVP		0.65
ClinPred		0.17	T
GERP RS		1.7
Varity_R		0.070
gMVP		0.044

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: rs1211529205; hg19: chr4-81123463; COSMIC: COSV99045645;