rs80257572

chr6-106107320-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001198.4(PRDM1):c.2312G>A(p.Gly771Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,614,068 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0082 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (20 hom.)
• Consequence: PRDM1 NM_001198.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.42

Genes affected

PRDM1 (HGNC:9346): (PR/SET domain 1) This gene encodes a protein that acts as a repressor of beta-interferon gene expression. The protein binds specifically to the PRDI (positive regulatory domain I element) of the beta-IFN gene promoter. Transcription of this gene increases upon virus induction. Two alternatively spliced transcript variants that encode different isoforms have been reported. [provided by RefSeq, Jul 2008]

ATG5 (HGNC:589): (autophagy related 5) The protein encoded by this gene, in combination with autophagy protein 12, functions as an E1-like activating enzyme in a ubiquitin-like conjugating system. The encoded protein is involved in several cellular processes, including autophagic vesicle formation, mitochondrial quality control after oxidative damage, negative regulation of the innate antiviral immune response, lymphocyte development and proliferation, MHC II antigen presentation, adipocyte differentiation, and apoptosis. Several transcript variants encoding different protein isoforms have been found for this gene. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033511221).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0082 (1248/152176) while in subpopulation AFR AF= 0.0268 (1114/41492). AF 95% confidence interval is 0.0255. There are 10 homozygotes in gnomad4. There are 577 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 1243 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM1	NM_001198.4	c.2312G>A	p.Gly771Asp	missense_variant	7/7	ENST00000369096.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM1	ENST00000369096.9	c.2312G>A	p.Gly771Asp	missense_variant	7/7	1	NM_001198.4	A1

Frequencies

GnomAD3 genomes AF: 0.00817 AC: 1243 AN: 152058 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00272 AC: 684 AN: 251484 Hom.: 10 AF XY: 0.00216 AC XY: 294 AN XY: 135920

Gnomad AFR exome AF: 0.0274

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000703

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00125 AC: 1830 AN: 1461892 Hom.: 20 Cov.: 31 AF XY: 0.00113 AC XY: 819 AN XY: 727246

Gnomad4 AFR exome AF: 0.0274

Gnomad4 AMR exome AF: 0.00389

Gnomad4 ASJ exome AF: 0.000650

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000469

Gnomad4 OTH exome AF: 0.00277

GnomAD4 genome AF: 0.00820 AC: 1248 AN: 152176 Hom.: 10 Cov.: 32 AF XY: 0.00776 AC XY: 577 AN XY: 74398

Gnomad4 AFR AF: 0.0268

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00222 Hom.: 4

Bravo AF: 0.00928

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0268 AC: 118

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00305 AC: 370

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000889

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	18
Dann	Benign	0.94
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.049
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.74	T;T;T;T
MetaRNN	Benign	0.0034	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.67	N;N;.;N
REVEL	Benign	0.051
Sift	Benign	0.18	T;T;.;T
Sift4G	Benign	0.54	T;T;.;T
Polyphen		0.059	.;B;.;.
Vest4		0.10
MVP		0.27
MPC		0.50
ClinPred		0.0047	T
GERP RS		2.6
Varity_R		0.062
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs80257572; hg19: chr6-106555195; COSMIC: COSV64844784; COSMIC: COSV64844784;