4-80201534-G-T

Variant names:

• chr4-80201534-G-T
• rs61999345
• NM_001099403.2:c.451+13G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001099403.2(PRDM8):​c.451+13G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,610,092 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (18 hom.)
• Consequence: PRDM8 NM_001099403.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.680
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-80201534-G-T is Benign according to our data. Variant chr4-80201534-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00814 (1240/152340) while in subpopulation AFR AF = 0.0279 (1162/41582). AF 95% confidence interval is 0.0266. There are 21 homozygotes in GnomAd4. There are 595 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

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.451+13G>T		intron	N/A	NP_001092873.1	Q9NQV8-1
	PRDM8	NM_020226.4		c.451+13G>T		intron	N/A	NP_064611.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM8	ENST00000415738.3	TSL:1 MANE Select	c.451+13G>T		intron	N/A	ENSP00000406998.2	Q9NQV8-1
	PRDM8	ENST00000339711.8	TSL:1	c.451+13G>T		intron	N/A	ENSP00000339764.4	Q9NQV8-1
	PRDM8	ENST00000515013.5	TSL:1	c.451+13G>T		intron	N/A	ENSP00000425149.1	E9PEH0

Frequencies

GnomAD3 genomes AF: 0.00807 AC: 1229 AN: 152222 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

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: 0.000118

Gnomad OTH AF: 0.00862

GnomAD2 exomes AF: 0.00234 AC: 580 AN: 248034 AF XY: 0.00187

Gnomad AFR exome AF: 0.0293

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.000797

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00105 AC: 1525 AN: 1457752 Hom.: 18 Cov.: 31 AF XY: 0.000995 AC XY: 722 AN XY: 725354

African (AFR) AF: 0.0324 AC: 1083 AN: 33378

American (AMR) AF: 0.00224 AC: 100 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00436 AC: 25 AN: 5738

European-Non Finnish (NFE) AF: 0.0000929 AC: 103 AN: 1108412

Other (OTH) AF: 0.00286 AC: 172 AN: 60242

GnomAD4 genome AF: 0.00814 AC: 1240 AN: 152340 Hom.: 21 Cov.: 32 AF XY: 0.00799 AC XY: 595 AN XY: 74488

African (AFR) AF: 0.0279 AC: 1162 AN: 41582

American (AMR) AF: 0.00340 AC: 52 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68038

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.00458 Hom.: 4

Bravo AF: 0.00936

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Early-onset Lafora body disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.84
DANN	Benign	0.46
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61999345;

hg19: chr4-81122688;