rs774459714

Variant names:

• chr4-80203136-T-C
• rs774459714
• NM_001099403.2:c.1674T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001099403.2(PRDM8):​c.1674T>C​(p.Gly558Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000898 in 1,558,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000092 (0 hom.)
• Consequence: PRDM8 NM_001099403.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0240
• Publications: 0 publications found

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]

PRDM8 Gene-Disease associations (from GenCC):

• early-onset Lafora body disease

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-80203136-T-C is Benign according to our data. Variant chr4-80203136-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 542344.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.024 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099403.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM8	NM_001099403.2	MANE Select	c.1674T>C	p.Gly558Gly	synonymous	Exon 4 of 4	NP_001092873.1
	PRDM8	NM_020226.4		c.1674T>C	p.Gly558Gly	synonymous	Exon 10 of 10	NP_064611.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM8	ENST00000415738.3	TSL:1 MANE Select	c.1674T>C	p.Gly558Gly	synonymous	Exon 4 of 4	ENSP00000406998.2
	PRDM8	ENST00000339711.8	TSL:1	c.1674T>C	p.Gly558Gly	synonymous	Exon 10 of 10	ENSP00000339764.4
	PRDM8	ENST00000952376.1		c.1677T>C	p.Gly559Gly	synonymous	Exon 4 of 4	ENSP00000622435.1

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150588 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000579 AC: 9 AN: 155416 AF XY: 0.0000347

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000329

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000923 AC: 13 AN: 1407728 Hom.: 0 Cov.: 36 AF XY: 0.00000573 AC XY: 4 AN XY: 697520

African (AFR) AF: 0.00 AC: 0 AN: 31526

American (AMR) AF: 0.000331 AC: 13 AN: 39308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25308

East Asian (EAS) AF: 0.00 AC: 0 AN: 36708

South Asian (SAS) AF: 0.00 AC: 0 AN: 81290

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5330

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092742

Other (OTH) AF: 0.00 AC: 0 AN: 58618

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150588 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73556

African (AFR) AF: 0.00 AC: 0 AN: 40946

American (AMR) AF: 0.0000658 AC: 1 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 4978

South Asian (SAS) AF: 0.00 AC: 0 AN: 4742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67474

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

Asia WGS AF: 0.000289 AC: 1 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Early-onset Lafora body disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.1
DANN	Benign	0.39
PhyloP100		-0.024

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

Other links and lift over

dbSNP: rs774459714; hg19: chr4-81124290;