4-80200197-T-C

Variant names:

• chr4-80200197-T-C
• rs369098269
• NM_001099403.2:c.117T>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.117T>C​(p.Ala39Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,614,150 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: PRDM8 NM_001099403.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.555
• 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=-0.52).
• BP6: Variant 4-80200197-T-C is Benign according to our data. Variant chr4-80200197-T-C is described in ClinVar as [Benign]. Clinvar id is 542342.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.555 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM8	NM_001099403.2	c.117T>C	p.Ala39Ala	synonymous_variant	Exon 2 of 4	ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4	c.117T>C	p.Ala39Ala	synonymous_variant	Exon 8 of 10		NP_064611.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM8	ENST00000415738.3	c.117T>C	p.Ala39Ala	synonymous_variant	Exon 2 of 4	1	NM_001099403.2	ENSP00000406998.2
PRDM8	ENST00000339711.8	c.117T>C	p.Ala39Ala	synonymous_variant	Exon 8 of 10	1		ENSP00000339764.4
PRDM8	ENST00000515013.5	c.117T>C	p.Ala39Ala	synonymous_variant	Exon 8 of 10	1		ENSP00000425149.1
PRDM8	ENST00000504452.5	c.117T>C	p.Ala39Ala	synonymous_variant	Exon 6 of 8	5		ENSP00000423985.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152198 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000228 AC: 57 AN: 249584 AF XY: 0.000222

Gnomad AFR exome AF: 0.000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000814 AC: 119 AN: 1461836 Hom.: 0 Cov.: 31 AF XY: 0.0000825 AC XY: 60 AN XY: 727232

African (AFR) AF: 0.000329 AC: 11 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00202 AC: 80 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111966

Other (OTH) AF: 0.000464 AC: 28 AN: 60396

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152314 Hom.: 0 Cov.: 31 AF XY: 0.000255 AC XY: 19 AN XY: 74486

African (AFR) AF: 0.000433 AC: 18 AN: 41576

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

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

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

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: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.000242

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early-onset Lafora body disease Benign:1

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	10
DANN	Benign	0.66
PhyloP100		-0.56
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

Other links and lift over

dbSNP: rs369098269; hg19: chr4-81121351;