chr4-80202184-C-A

Position:

chr4-80202184-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001099403.2(PRDM8):c.722C>A(p.Pro241Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000935 in 1,612,002 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 8 hom., cov: 31)

Exomes 𝑓: 0.00055 ( 7 hom. )

Consequence

PRDM8
NM_001099403.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.11

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 4-80202184-C-A is Benign according to our data. Variant chr4-80202184-C-A is described in ClinVar as [Benign]. Clinvar id is 475684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000548 (800/1460396) while in subpopulation AFR AF= 0.0164 (549/33474). AF 95% confidence interval is 0.0153. There are 7 homozygotes in gnomad4_exome. There are 372 alleles in male gnomad4_exome subpopulation. Median coverage is 38. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM8	NM_001099403.2 linkuse as main transcript	c.722C>A	p.Pro241Gln	missense_variant	4/4	ENST00000415738.3	NP_001092873.1	Q9NQV8-1A0A024RDC4Q05CA1
PRDM8	NM_020226.4 linkuse as main transcript	c.722C>A	p.Pro241Gln	missense_variant	10/10		NP_064611.3	Q9NQV8-1A0A024RDC4Q05CA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PRDM8	ENST00000415738.3 linkuse as main transcript	c.722C>A	p.Pro241Gln	missense_variant	4/4	1	NM_001099403.2	ENSP00000406998.2	Q9NQV8-1
PRDM8	ENST00000339711.8 linkuse as main transcript	c.722C>A	p.Pro241Gln	missense_variant	10/10	1		ENSP00000339764.4	Q9NQV8-1
PRDM8	ENST00000515013.5 linkuse as main transcript	c.722C>A	p.Pro241Gln	missense_variant	10/10	1		ENSP00000425149.1	E9PEH0
PRDM8	ENST00000504452.5 linkuse as main transcript	c.722C>A	p.Pro241Gln	missense_variant	8/8	5		ENSP00000423985.1	Q9NQV8-1

Frequencies

GnomAD3 genomes

AF:

0.00463

AC:

702

AN:

151490

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0000884

Gnomad OTH

AF:

0.00432

GnomAD3 exomes

AF:

0.00120

AC:

289

AN:

240016

Hom.:

AF XY:

0.000964

AC XY:

127

AN XY:

131718

show subpopulations

Gnomad AFR exome

AF:

0.0164

Gnomad AMR exome

AF:

0.00111

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000987

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000339

GnomAD4 exome

AF:

0.000548

AC:

800

AN:

1460396

Hom.:

Cov.:

AF XY:

0.000512

AC XY:

372

AN XY:

726518

show subpopulations

Gnomad4 AFR exome

AF:

0.0164

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000800

Gnomad4 OTH exome

AF:

0.00137

GnomAD4 genome

AF:

0.00466

AC:

707

AN:

151606

Hom.:

Cov.:

AF XY:

0.00453

AC XY:

336

AN XY:

74114

show subpopulations

Gnomad4 AFR

AF:

0.0160

Gnomad4 AMR

AF:

0.00190

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000884

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00203

Hom.:

Bravo

AF:

0.00520

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00134

AC:

160

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Early-onset Lafora body disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Benign

0.80

DEOGEN2

Benign

0.027

T;.;T;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.56

.;T;T;.

MetaRNN

Benign

0.0056

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.97

L;.;L;L

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.4

N;D;N;N

REVEL

Benign

0.13

Sift

Benign

0.092

T;T;T;T

Sift4G

Benign

0.18

T;T;T;T

Polyphen

0.050

B;.;B;B

Vest4

0.10

MVP

0.71

ClinPred

0.018

GERP RS

3.8

Varity_R

0.10

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.33

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.33

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over