6-106105017-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001198.4(PRDM1):c.857G>C(p.Arg286Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00572 in 1,614,046 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (50 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (90 hom.)
• Consequence: PRDM1 NM_001198.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 3.73

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022687912).
• BP6: Variant 6-106105017-G-C is Benign according to our data. Variant chr6-106105017-G-C is described in ClinVar as [Benign]. Clinvar id is 135085.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.016 (2427/152158) while in subpopulation AFR AF= 0.0456 (1891/41490). AF 95% confidence interval is 0.0439. There are 50 homozygotes in gnomad4. There are 1192 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2429 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM1	NM_001198.4	c.857G>C	p.Arg286Pro	missense_variant	5/7	ENST00000369096.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM1	ENST00000369096.9	c.857G>C	p.Arg286Pro	missense_variant	5/7	1	NM_001198.4	A1

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2429 AN: 152040 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.0457

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00244

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00880 AC: 2213 AN: 251452 Hom.: 37 AF XY: 0.00850 AC XY: 1155 AN XY: 135916

Gnomad AFR exome AF: 0.0468

Gnomad AMR exome AF: 0.00700

Gnomad ASJ exome AF: 0.0248

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0178

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00298

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00466 AC: 6811 AN: 1461888 Hom.: 90 Cov.: 32 AF XY: 0.00492 AC XY: 3578 AN XY: 727244

Gnomad4 AFR exome AF: 0.0497

Gnomad4 AMR exome AF: 0.00700

Gnomad4 ASJ exome AF: 0.0267

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0169

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00173

Gnomad4 OTH exome AF: 0.00892

GnomAD4 genome AF: 0.0160 AC: 2427 AN: 152158 Hom.: 50 Cov.: 32 AF XY: 0.0160 AC XY: 1192 AN XY: 74396

Gnomad4 AFR AF: 0.0456

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0150

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00244

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00482 Hom.: 5

Bravo AF: 0.0176

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0470 AC: 207

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00932 AC: 1132

Asia WGS AF: 0.00953 AC: 34 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00379

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	16
Dann	Benign	0.93
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.36	T;T;T;T;T
MetaRNN	Benign	0.0023	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.060	N;N;.;N;N
REVEL	Benign	0.14
Sift	Benign	0.12	T;T;.;D;T
Sift4G	Benign	0.22	T;T;.;T;T
Polyphen		0.0060	.;B;.;.;.
Vest4		0.13
MVP		0.25
MPC		0.56
ClinPred		0.0063	T
GERP RS		4.4
Varity_R		0.16
gMVP		0.25

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: rs17066588; hg19: chr6-106552892; COSMIC: COSV64846428; COSMIC: COSV64846428;