rs143040512

Variant names:

• chr6-106105221-G-A
• rs143040512
• NM_001198.4:c.1061G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 publications found

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]

ATG5 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia, autosomal recessive 25

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 1536 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001198.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM1	NM_001198.4	MANE Select	c.1061G>A	p.Ser354Asn	missense	Exon 5 of 7	NP_001189.2
	PRDM1	NM_182907.3		c.659G>A	p.Ser220Asn	missense	Exon 3 of 5	NP_878911.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM1	ENST00000369096.9	TSL:1 MANE Select	c.1061G>A	p.Ser354Asn	missense	Exon 5 of 7	ENSP00000358092.4
	PRDM1	ENST00000369091.6	TSL:1	c.953G>A	p.Ser318Asn	missense	Exon 5 of 7	ENSP00000358087.2
	PRDM1	ENST00000369089.3	TSL:1	c.659G>A	p.Ser220Asn	missense	Exon 3 of 5	ENSP00000358085.3

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

GnomAD2 exomes AF: 0.0110 AC: 2752 AN: 250466 AF XY: 0.0116

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 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

African (AFR) AF: 0.00272 AC: 91 AN: 33480

American (AMR) AF: 0.00850 AC: 380 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00723 AC: 189 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00228 AC: 197 AN: 86258

European-Finnish (FIN) AF: 0.00631 AC: 335 AN: 53068

Middle Eastern (MID) AF: 0.0251 AC: 145 AN: 5766

European-Non Finnish (NFE) AF: 0.0168 AC: 18663 AN: 1111980

Other (OTH) AF: 0.0135 AC: 813 AN: 60390

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

African (AFR) AF: 0.00250 AC: 104 AN: 41524

American (AMR) AF: 0.00981 AC: 150 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.00443 AC: 47 AN: 10598

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0168 AC: 1143 AN: 68010

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.0157 Hom.: 23

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

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.10
Sift	Benign	0.11	T
Sift4G	Benign	0.37	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
Mutation Taster		=90/10	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: rs143040512; hg19: chr6-106553096; COSMIC: COSV64846844; COSMIC: COSV64846844;