4-80184069-G-T

Variant names:

• chr4-80184069-G-T
• rs2292849
• ENST00000503589.1:n.422-645C>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000508965.5(PRDM8):​n.177+14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 152,758 control chromosomes in the GnomAD database, including 2,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (2008 hom., cov: 32)
  • Exomes 𝑓: 0.094 (8 hom.)
• Consequence: PRDM8 ENST00000508965.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00300

Genes affected

PRDM8-AS1 (HGNC:55581): (PRDM8 antisense RNA 1)

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 (BayesDel_noAF=-0.82).
• BP6: Variant 4-80184069-G-T is Benign according to our data. Variant chr4-80184069-G-T is described in ClinVar as [Benign]. Clinvar id is 3256813.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM8-AS1	NR_183911.1	n.797-645C>A		intron_variant	Intron 5 of 5
PRDM8-AS1	NR_183912.1	n.794-645C>A		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM8-AS1	ENST00000503589.1	n.422-645C>A		intron_variant	Intron 1 of 1	4
PRDM8	ENST00000508965.5	n.177+14G>T		intron_variant	Intron 1 of 3	3
PRDM8	ENST00000509375.5	n.175+14G>T		intron_variant	Intron 1 of 2	3
PRDM8-AS1	ENST00000653209.1	n.892-645C>A		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19333 AN: 152096 Hom.: 2003 Cov.: 32

Gnomad AFR AF: 0.0944

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.559

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0794

Gnomad OTH AF: 0.129

GnomAD4 exome AF: 0.0938 AC: 51 AN: 544 Hom.: 8 Cov.: 0 AF XY: 0.0990 AC XY: 41 AN XY: 414

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.125

Gnomad4 EAS exome AF: 0.875

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.0591

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.127 AC: 19360 AN: 152214 Hom.: 2008 Cov.: 32 AF XY: 0.137 AC XY: 10212 AN XY: 74436

Gnomad4 AFR AF: 0.0944

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.560

Gnomad4 SAS AF: 0.268

Gnomad4 FIN AF: 0.168

Gnomad4 NFE AF: 0.0794

Gnomad4 OTH AF: 0.133

Alfa AF: 0.0432 Hom.: 40

Bravo AF: 0.129

Asia WGS AF: 0.422 AC: 1464 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 37% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 34. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.0
DANN	Benign	0.57

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2292849; hg19: chr4-81105223;