rs1211529205

Variant names:

• chr4-80202309-C-A
• rs1211529205
• NM_001099403.2:c.847C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-80202309-C-A
• chr4-80202309-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001099403.2(PRDM8):​c.847C>A​(p.Leu283Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 146,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000014 (0 hom., cov: 31)
• Consequence: PRDM8 NM_001099403.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24
• Publications: 0 publications found

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]

PRDM8 Gene-Disease associations (from GenCC):

• early-onset Lafora body disease

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07109249).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099403.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM8	NM_001099403.2	MANE Select	c.847C>A	p.Leu283Ile	missense	Exon 4 of 4	NP_001092873.1	Q9NQV8-1
	PRDM8	NM_020226.4		c.847C>A	p.Leu283Ile	missense	Exon 10 of 10	NP_064611.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM8	ENST00000415738.3	TSL:1 MANE Select	c.847C>A	p.Leu283Ile	missense	Exon 4 of 4	ENSP00000406998.2	Q9NQV8-1
	PRDM8	ENST00000339711.8	TSL:1	c.847C>A	p.Leu283Ile	missense	Exon 10 of 10	ENSP00000339764.4	Q9NQV8-1
	PRDM8	ENST00000515013.5	TSL:1	c.847C>A	p.Leu283Ile	missense	Exon 10 of 10	ENSP00000425149.1	E9PEH0

Frequencies

GnomAD3 genomes AF: 0.0000137 AC: 2 AN: 146230 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000512

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome AF: 0.0000137 AC: 2 AN: 146230 Hom.: 0 Cov.: 31 AF XY: 0.0000140 AC XY: 1 AN XY: 71392

African (AFR) AF: 0.0000512 AC: 2 AN: 39100

American (AMR) AF: 0.00 AC: 0 AN: 14844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3410

East Asian (EAS) AF: 0.00 AC: 0 AN: 4792

South Asian (SAS) AF: 0.00 AC: 0 AN: 4606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66376

Other (OTH) AF: 0.00 AC: 0 AN: 2008

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Early-onset Lafora body disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.0063	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.055
Sift	Benign	0.13	T
Sift4G	Benign	0.19	T
Polyphen		0.056	B
Vest4		0.13
MutPred		0.093		Gain of glycosylation at S278 (P = 0.0087)
MVP		0.37
ClinPred		0.085	T
GERP RS		1.7
Varity_R		0.062
gMVP		0.025
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1211529205; hg19: chr4-81123463;