rs143040512

Positions:

• chr6-106105221-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.1061G>A​(p.Ser354Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,613,678 control chromosomes in the GnomAD database, including 203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.010 (7 hom., cov: 32)
  • Exomes 𝑓: 0.014 (196 hom.)
• Consequence: PRDM1 NM_001198.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 9.36

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=0.0060581267).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0101 (1536/152190) while in subpopulation NFE AF= 0.0168 (1143/68010). AF 95% confidence interval is 0.016. There are 7 homozygotes in gnomad4. There are 709 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 1536 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM1	NM_001198.4	c.1061G>A	p.Ser354Asn	missense_variant	5/7	ENST00000369096.9	NP_001189.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM1	ENST00000369096.9	c.1061G>A	p.Ser354Asn	missense_variant	5/7	1	NM_001198.4	ENSP00000358092	A1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1539 AN: 152072 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00989

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0110 AC: 2752 AN: 250466 Hom.: 25 AF XY: 0.0116 AC XY: 1566 AN XY: 135494

Gnomad AFR exome AF: 0.00284

Gnomad AMR exome AF: 0.00781

Gnomad ASJ exome AF: 0.00796

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00239

Gnomad FIN exome AF: 0.00489

Gnomad NFE exome AF: 0.0184

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0142 AC: 20813 AN: 1461488 Hom.: 196 Cov.: 32 AF XY: 0.0139 AC XY: 10141 AN XY: 727070

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.00850

Gnomad4 ASJ exome AF: 0.00723

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00228

Gnomad4 FIN exome AF: 0.00631

Gnomad4 NFE exome AF: 0.0168

Gnomad4 OTH exome AF: 0.0135

GnomAD4 genome AF: 0.0101 AC: 1536 AN: 152190 Hom.: 7 Cov.: 32 AF XY: 0.00953 AC XY: 709 AN XY: 74418

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.00981

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.0168

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0147 Hom.: 4

Bravo AF: 0.0110

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0140 AC: 54

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0177 AC: 152

ExAC AF: 0.0109 AC: 1324

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0170

EpiControl AF: 0.0199

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;T;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;D;D
MetaRNN	Benign	0.0061	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	.;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N;N;.;N
REVEL	Benign	0.10
Sift	Benign	0.11	T;T;.;T
Sift4G	Benign	0.37	T;T;.;T
Polyphen		0.11	.;B;.;.
Vest4		0.11
MPC		0.44
ClinPred		0.087	T
GERP RS		5.2
Varity_R		0.19
gMVP		0.28

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: rs143040512; hg19: chr6-106553096; COSMIC: COSV64846844; COSMIC: COSV64846844;