rs200010979

chr4-80202184-C-Achr4-80202184-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate 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 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 criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.11

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 Benign. Variant got -10 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]. Clinvar id is 475684.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome 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 gnomad4_exome. There are 372 alleles in male gnomad4_exome subpopulation. Median coverage is 38. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM8	NM_001099403.2	c.722C>A	p.Pro241Gln	missense_variant	4/4	ENST00000415738.3
PRDM8	NM_020226.4	c.722C>A	p.Pro241Gln	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM8	ENST00000415738.3	c.722C>A	p.Pro241Gln	missense_variant	4/4	1	NM_001099403.2	P1
PRDM8	ENST00000339711.8	c.722C>A	p.Pro241Gln	missense_variant	10/10	1		P1
PRDM8	ENST00000515013.5	c.722C>A	p.Pro241Gln	missense_variant	10/10	1
PRDM8	ENST00000504452.5	c.722C>A	p.Pro241Gln	missense_variant	8/8	5		P1

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

GnomAD3 exomes AF: 0.00120 AC: 289 AN: 240016 Hom.: 4 AF XY: 0.000964 AC XY: 127 AN XY: 131718

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 SAS exome AF: 0.0000987

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

Gnomad4 AFR exome AF: 0.0164

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000800

Gnomad4 OTH exome AF: 0.00137

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

Gnomad4 AFR AF: 0.0160

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000884

Gnomad4 OTH AF: 0.00427

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early-onset Lafora body disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;.;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.84	D
MetaRNN	Benign	0.0056	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.97	L;.;L;L
MutationTaster	Benign	0.75	N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.4	N;D;N;N
REVEL	Benign	0.13
Sift	Benign	0.092	T;T;T;T
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.050	B;.;B;B
Vest4		0.10
MVP		0.71
ClinPred		0.018	T
GERP RS		3.8
Varity_R		0.10
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs200010979; hg19: chr4-81123338;