rs575791037

Variant names:

• chr4-80202874-G-A
• rs575791037
• NM_001099403.2:c.1412G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001099403.2(PRDM8):​c.1412G>A​(p.Ser471Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,274,036 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (2 hom.)
• Consequence: PRDM8 NM_001099403.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.300
• 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003796935).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.1412G>A	p.Ser471Asn	missense	Exon 4 of 4	NP_001092873.1	Q9NQV8-1
	PRDM8	NM_020226.4		c.1412G>A	p.Ser471Asn	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.1412G>A	p.Ser471Asn	missense	Exon 4 of 4	ENSP00000406998.2	Q9NQV8-1
	PRDM8	ENST00000339711.8	TSL:1	c.1412G>A	p.Ser471Asn	missense	Exon 10 of 10	ENSP00000339764.4	Q9NQV8-1
	PRDM8	ENST00000952376.1		c.1415G>A	p.Ser472Asn	missense	Exon 4 of 4	ENSP00000622435.1

Frequencies

GnomAD3 genomes AF: 0.000583 AC: 88 AN: 150984 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00165

Gnomad ASJ AF: 0.000868

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000576

Gnomad OTH AF: 0.000962

GnomAD2 exomes AF: 0.00633 AC: 1 AN: 158 AF XY: 0.0111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00658

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000419 AC: 470 AN: 1122944 Hom.: 2 Cov.: 36 AF XY: 0.000506 AC XY: 273 AN XY: 539100

African (AFR) AF: 0.0000444 AC: 1 AN: 22540

American (AMR) AF: 0.000625 AC: 5 AN: 8000

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 6 AN: 14236

East Asian (EAS) AF: 0.00 AC: 0 AN: 25368

South Asian (SAS) AF: 0.00429 AC: 129 AN: 30090

European-Finnish (FIN) AF: 0.0000834 AC: 2 AN: 23982

Middle Eastern (MID) AF: 0.00200 AC: 6 AN: 2996

European-Non Finnish (NFE) AF: 0.000309 AC: 294 AN: 950584

Other (OTH) AF: 0.000598 AC: 27 AN: 45148

GnomAD4 genome AF: 0.000576 AC: 87 AN: 151092 Hom.: 0 Cov.: 32 AF XY: 0.000569 AC XY: 42 AN XY: 73838

African (AFR) AF: 0.000121 AC: 5 AN: 41412

American (AMR) AF: 0.00165 AC: 25 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.000868 AC: 3 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000576 AC: 39 AN: 67658

Other (OTH) AF: 0.000952 AC: 2 AN: 2100

Alfa AF: 0.000693 Hom.: 0

Bravo AF: 0.000518

ClinVar

ClinVar submissions as Germline

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	0.099
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.30
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.0070
Sift	Benign	0.46	T
Sift4G	Benign	0.27	T
Polyphen		0.0080	B
Vest4		0.042
MVP		0.41
ClinPred		0.026	T
GERP RS		1.6
Varity_R		0.051
gMVP		0.099
Mutation Taster		=100/0	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: rs575791037; hg19: chr4-81124028;