chr4-80202184-C-A

Variant names:

• chr4-80202184-C-A
• rs200010979
• NM_001099403.2:c.722C>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001099403.2(PRDM8):​c.722C>A​(p.Pro241Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000935 in 1,612,002 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P241S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 31)
  • Exomes 𝑓: 0.00055 (7 hom.)
• Consequence: PRDM8 NM_001099403.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.11
• 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 -16 ACMG points.

• BP6: Variant 4-80202184-C-A is Benign according to our data. Variant chr4-80202184-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000548 (800/1460396) while in subpopulation AFR AF = 0.0164 (549/33474). AF 95% confidence interval is 0.0153. There are 7 homozygotes in GnomAdExome4. There are 372 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM8	NM_001099403.2	MANE Select	c.722C>A	p.Pro241Gln	missense	Exon 4 of 4	NP_001092873.1
	PRDM8	NM_020226.4		c.722C>A	p.Pro241Gln	missense	Exon 10 of 10	NP_064611.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM8	ENST00000415738.3	TSL:1 MANE Select	c.722C>A	p.Pro241Gln	missense	Exon 4 of 4	ENSP00000406998.2
	PRDM8	ENST00000339711.8	TSL:1	c.722C>A	p.Pro241Gln	missense	Exon 10 of 10	ENSP00000339764.4
	PRDM8	ENST00000515013.5	TSL:1	c.722C>A	p.Pro241Gln	missense	Exon 10 of 10	ENSP00000425149.1

Frequencies

GnomAD3 genomes AF: 0.00463 AC: 702 AN: 151490 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.00432

GnomAD2 exomes AF: 0.00120 AC: 289 AN: 240016 AF XY: 0.000964

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000339

GnomAD4 exome AF: 0.000548 AC: 800 AN: 1460396 Hom.: 7 Cov.: 38 AF XY: 0.000512 AC XY: 372 AN XY: 726518

African (AFR) AF: 0.0164 AC: 549 AN: 33474

American (AMR) AF: 0.00121 AC: 54 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52094

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0000800 AC: 89 AN: 1111914

Other (OTH) AF: 0.00137 AC: 83 AN: 60372

GnomAD4 genome AF: 0.00466 AC: 707 AN: 151606 Hom.: 8 Cov.: 31 AF XY: 0.00453 AC XY: 336 AN XY: 74114

African (AFR) AF: 0.0160 AC: 661 AN: 41356

American (AMR) AF: 0.00190 AC: 29 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10490

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0000884 AC: 6 AN: 67836

Other (OTH) AF: 0.00427 AC: 9 AN: 2106

Alfa AF: 0.00203 Hom.: 1

Bravo AF: 0.00520

ESP6500AA AF: 0.0109 AC: 38

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00134 AC: 160

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Early-onset Lafora body disease (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	24
DANN	Benign	0.80
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.13
Sift	Benign	0.092	T
Sift4G	Benign	0.18	T
Polyphen		0.050	B
Vest4		0.10
MVP		0.71
ClinPred		0.018	T
GERP RS		3.8
Varity_R		0.10
gMVP		0.15
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: 2

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

Other links and lift over

dbSNP: rs200010979; hg19: chr4-81123338;