4-80202776-C-T

Position:

• chr4-80202776-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001099403.2(PRDM8):​c.1314C>T​(p.Ala438Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 1,249,798 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (61 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (45 hom.)
• Consequence: PRDM8 NM_001099403.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0210

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 4-80202776-C-T is Benign according to our data. Variant chr4-80202776-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 475666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.021 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM8	NM_001099403.2	c.1314C>T	p.Ala438Ala	synonymous_variant	4/4	ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4	c.1314C>T	p.Ala438Ala	synonymous_variant	10/10		NP_064611.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM8	ENST00000415738.3	c.1314C>T	p.Ala438Ala	synonymous_variant	4/4	1	NM_001099403.2	ENSP00000406998.2
PRDM8	ENST00000339711.8	c.1314C>T	p.Ala438Ala	synonymous_variant	10/10	1		ENSP00000339764.4
PRDM8	ENST00000504452.5	c.1314C>T	p.Ala438Ala	synonymous_variant	8/8	5		ENSP00000423985.1
PRDM8	ENST00000515013.5	c.*31C>T		downstream_gene_variant		1		ENSP00000425149.1

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2511 AN: 151314 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0565

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00665

Gnomad ASJ AF: 0.00376

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000966

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000295

Gnomad OTH AF: 0.0168

GnomAD4 exome AF: 0.00172 AC: 1890 AN: 1098376 Hom.: 45 Cov.: 36 AF XY: 0.00159 AC XY: 827 AN XY: 520650

Gnomad4 AFR exome AF: 0.0588

Gnomad4 AMR exome AF: 0.00550

Gnomad4 ASJ exome AF: 0.00558

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000168

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000224

Gnomad4 OTH exome AF: 0.00453

GnomAD4 genome AF: 0.0166 AC: 2511 AN: 151422 Hom.: 61 Cov.: 32 AF XY: 0.0158 AC XY: 1167 AN XY: 73992

Gnomad4 AFR AF: 0.0564

Gnomad4 AMR AF: 0.00658

Gnomad4 ASJ AF: 0.00376

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000966

Gnomad4 NFE AF: 0.000295

Gnomad4 OTH AF: 0.0167

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.0189

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early-onset Lafora body disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	11
DANN	Benign	0.92

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: rs188061449; hg19: chr4-81123930;