4-80202687-G-C

Variant summary

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

The NM_001099403.2(PRDM8):c.1225G>C(p.Val409Leu) 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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V409I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRDM8 NM_001099403.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0470

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=0.073845506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM8	NM_001099403.2	c.1225G>C	p.Val409Leu	missense_variant	4/4	ENST00000415738.3
PRDM8	NM_020226.4	c.1225G>C	p.Val409Leu	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM8	ENST00000415738.3	c.1225G>C	p.Val409Leu	missense_variant	4/4	1	NM_001099403.2	P1
PRDM8	ENST00000339711.8	c.1225G>C	p.Val409Leu	missense_variant	10/10	1		P1
PRDM8	ENST00000515013.5	c.1225G>C	p.Val409Leu	missense_variant	10/10	1
PRDM8	ENST00000504452.5	c.1225G>C	p.Val409Leu	missense_variant	8/8	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	1.7
Dann	Benign	0.86
DEOGEN2	Benign	0.0079	T;.;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.13	N
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.074	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.090	N;N;N;N
REVEL	Benign	0.047
Sift	Benign	0.43	T;T;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.0050	B;.;B;B
Vest4		0.034
MutPred		0.085		Gain of glycosylation at S411 (P = 0.1055);Gain of glycosylation at S411 (P = 0.1055);Gain of glycosylation at S411 (P = 0.1055);Gain of glycosylation at S411 (P = 0.1055);
MVP		0.45
ClinPred		0.024	T
GERP RS		1.2
Varity_R		0.037
gMVP		0.052

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: rs1483533129; hg19: chr4-81123841;