4-80202909-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001099403.2(PRDM8):c.1447G>T(p.Ala483Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000937 in 1,338,846 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict 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. A483T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (4 hom.)
• Consequence: PRDM8 NM_001099403.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.387

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015520751).
• BP6: Variant 4-80202909-G-T is Benign according to our data. Variant chr4-80202909-G-T is described in ClinVar as [Benign]. Clinvar id is 475669.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00471 (713/151318) while in subpopulation AFR AF= 0.0161 (667/41448). AF 95% confidence interval is 0.0151. There are 8 homozygotes in gnomad4. There are 336 alleles in male gnomad4 subpopulation. Median coverage is 32. 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.1447G>T	p.Ala483Ser	missense_variant	4/4	ENST00000415738.3
PRDM8	NM_020226.4	c.1447G>T	p.Ala483Ser	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM8	ENST00000415738.3	c.1447G>T	p.Ala483Ser	missense_variant	4/4	1	NM_001099403.2	P1
PRDM8	ENST00000339711.8	c.1447G>T	p.Ala483Ser	missense_variant	10/10	1		P1
PRDM8	ENST00000504452.5	c.1447G>T	p.Ala483Ser	missense_variant	8/8	5		P1

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 708 AN: 151210 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00191

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: 0.0000885

Gnomad OTH AF: 0.00432

GnomAD3 exomes AF: 0.00212 AC: 9 AN: 4236 Hom.: 1 AF XY: 0.00140 AC XY: 4 AN XY: 2852

Gnomad AFR exome AF: 0.0473

Gnomad AMR exome AF: 0.00518

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000456 AC: 541 AN: 1187528 Hom.: 4 Cov.: 36 AF XY: 0.000435 AC XY: 251 AN XY: 577150

Gnomad4 AFR exome AF: 0.0163

Gnomad4 AMR exome AF: 0.00164

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000136

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000587

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.00471 AC: 713 AN: 151318 Hom.: 8 Cov.: 32 AF XY: 0.00454 AC XY: 336 AN XY: 73966

Gnomad4 AFR AF: 0.0161

Gnomad4 AMR AF: 0.00191

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000885

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00319 Hom.: 0

ExAC AF: 0.000321 AC: 6

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	0.068
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	1.9
Dann	Benign	0.76
DEOGEN2	Benign	0.0063	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.058	N
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.11	N;N;N
REVEL	Benign	0.022
Sift	Benign	0.52	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.11
MVP		0.43
ClinPred		0.0048	T
GERP RS		1.9
Varity_R		0.060
gMVP		0.20

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: rs544862921; hg19: chr4-81124063;