4-80202449-G-T

Variant names:

• chr4-80202449-G-T
• rs6831357
• NM_001099403.2:c.987G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001099403.2(PRDM8):​c.987G>T​(p.Leu329Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,546,432 control chromosomes in the GnomAD database, including 1,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L329L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.062 (952 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (813 hom.)
• Consequence: PRDM8 NM_001099403.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.10

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 4-80202449-G-T is Benign according to our data. Variant chr4-80202449-G-T is described in ClinVar as [Benign]. Clinvar id is 475686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM8	NM_001099403.2	c.987G>T	p.Leu329Leu	synonymous_variant	Exon 4 of 4	ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4	c.987G>T	p.Leu329Leu	synonymous_variant	Exon 10 of 10		NP_064611.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM8	ENST00000415738.3	c.987G>T	p.Leu329Leu	synonymous_variant	Exon 4 of 4	1	NM_001099403.2	ENSP00000406998.2
PRDM8	ENST00000339711.8	c.987G>T	p.Leu329Leu	synonymous_variant	Exon 10 of 10	1		ENSP00000339764.4
PRDM8	ENST00000515013.5	c.987G>T	p.Leu329Leu	synonymous_variant	Exon 10 of 10	1		ENSP00000425149.1
PRDM8	ENST00000504452.5	c.987G>T	p.Leu329Leu	synonymous_variant	Exon 8 of 8	5		ENSP00000423985.1

Frequencies

GnomAD3 genomes AF: 0.0616 AC: 9363 AN: 151908 Hom.: 944 Cov.: 32

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000779

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.000986

Gnomad OTH AF: 0.0489

GnomAD2 exomes AF: 0.0133 AC: 1878 AN: 141084 AF XY: 0.0108

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.0139

Gnomad ASJ exome AF: 0.000974

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00871

GnomAD4 exome AF: 0.00675 AC: 9413 AN: 1394406 Hom.: 813 Cov.: 37 AF XY: 0.00603 AC XY: 4147 AN XY: 688014

Gnomad4 AFR exome AF: 0.223 AC: 6997 AN: 31416

Gnomad4 AMR exome AF: 0.0149 AC: 528 AN: 35328

Gnomad4 ASJ exome AF: 0.00116 AC: 29 AN: 25090

Gnomad4 EAS exome AF: 0.0000839 AC: 3 AN: 35762

Gnomad4 SAS exome AF: 0.000669 AC: 53 AN: 79246

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 45540

Gnomad4 NFE exome AF: 0.000669 AC: 722 AN: 1078726

Gnomad4 Remaining exome AF: 0.0169 AC: 979 AN: 57832

GnomAD4 genome AF: 0.0618 AC: 9396 AN: 152026 Hom.: 952 Cov.: 32 AF XY: 0.0596 AC XY: 4434 AN XY: 74342

Gnomad4 AFR AF: 0.210 AC: 0.21045 AN: 0.21045

Gnomad4 AMR AF: 0.0313 AC: 0.0313277 AN: 0.0313277

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000781 AC: 0.000780945 AN: 0.000780945

Gnomad4 SAS AF: 0.000831 AC: 0.000830565 AN: 0.000830565

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000986 AC: 0.000985961 AN: 0.000985961

Gnomad4 OTH AF: 0.0502 AC: 0.050237 AN: 0.050237

Alfa AF: 0.00395 Hom.: 9

Bravo AF: 0.0707

Asia WGS AF: 0.0300 AC: 104 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early-onset Lafora body disease Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.6
DANN	Benign	0.74
Mutation Taster		=100/0	polymorphism (auto)

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: rs6831357; hg19: chr4-81123603;