4-80201534-G-T

Position:

• chr4-80201534-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001099403.2(PRDM8):​c.451+13G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,610,092 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (18 hom.)
• Consequence: PRDM8 NM_001099403.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.680

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-80201534-G-T is Benign according to our data. Variant chr4-80201534-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 445962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00814 (1240/152340) while in subpopulation AFR AF= 0.0279 (1162/41582). AF 95% confidence interval is 0.0266. There are 21 homozygotes in gnomad4. There are 595 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM8	NM_001099403.2	c.451+13G>T		intron_variant		ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4	c.451+13G>T		intron_variant			NP_064611.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM8	ENST00000415738.3	c.451+13G>T		intron_variant		1	NM_001099403.2	ENSP00000406998	P1
PRDM8	ENST00000339711.8	c.451+13G>T		intron_variant		1		ENSP00000339764	P1
PRDM8	ENST00000515013.5	c.451+13G>T		intron_variant		1		ENSP00000425149
PRDM8	ENST00000504452.5	c.451+13G>T		intron_variant		5		ENSP00000423985	P1

Frequencies

GnomAD3 genomes AF: 0.00807 AC: 1229 AN: 152222 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

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: 0.000118

Gnomad OTH AF: 0.00862

GnomAD3 exomes AF: 0.00234 AC: 580 AN: 248034 Hom.: 8 AF XY: 0.00187 AC XY: 252 AN XY: 134804

Gnomad AFR exome AF: 0.0293

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.000797

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00105 AC: 1525 AN: 1457752 Hom.: 18 Cov.: 31 AF XY: 0.000995 AC XY: 722 AN XY: 725354

Gnomad4 AFR exome AF: 0.0324

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000929

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.00814 AC: 1240 AN: 152340 Hom.: 21 Cov.: 32 AF XY: 0.00799 AC XY: 595 AN XY: 74488

Gnomad4 AFR AF: 0.0279

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00853

Alfa AF: 0.00488 Hom.: 1

Bravo AF: 0.00936

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2017	- -

Early-onset Lafora body disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.84
DANN	Benign	0.46

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: rs61999345; hg19: chr4-81122688;