4-80202776-C-T

Variant names:

• chr4-80202776-C-T
• rs188061449
• NM_001099403.2:c.1314C>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.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
• 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.1314C>T	p.Ala438Ala	synonymous	Exon 4 of 4	NP_001092873.1	Q9NQV8-1
	PRDM8	NM_020226.4		c.1314C>T	p.Ala438Ala	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.1314C>T	p.Ala438Ala	synonymous	Exon 4 of 4	ENSP00000406998.2	Q9NQV8-1
	PRDM8	ENST00000339711.8	TSL:1	c.1314C>T	p.Ala438Ala	synonymous	Exon 10 of 10	ENSP00000339764.4	Q9NQV8-1
	PRDM8	ENST00000952376.1		c.1317C>T	p.Ala439Ala	synonymous	Exon 4 of 4	ENSP00000622435.1

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 120 AF XY: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.0588 AC: 1331 AN: 22632

American (AMR) AF: 0.00550 AC: 45 AN: 8180

Ashkenazi Jewish (ASJ) AF: 0.00558 AC: 80 AN: 14344

East Asian (EAS) AF: 0.00 AC: 0 AN: 25884

South Asian (SAS) AF: 0.000168 AC: 4 AN: 23846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22532

Middle Eastern (MID) AF: 0.00639 AC: 19 AN: 2974

European-Non Finnish (NFE) AF: 0.000224 AC: 209 AN: 933438

Other (OTH) AF: 0.00453 AC: 202 AN: 44546

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

African (AFR) AF: 0.0564 AC: 2336 AN: 41412

American (AMR) AF: 0.00658 AC: 100 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00376 AC: 13 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5078

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.0000966 AC: 1 AN: 10356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000295 AC: 20 AN: 67788

Other (OTH) AF: 0.0167 AC: 35 AN: 2102

Alfa AF: 0.00291 Hom.: 0

Bravo AF: 0.0189

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Early-onset Lafora body disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	11
DANN	Benign	0.92
PhyloP100		0.021
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

Other links and lift over

dbSNP: rs188061449; hg19: chr4-81123930;