chr6-106107320-G-A

Variant names:

• chr6-106107320-G-A
• rs80257572
• NM_001198.4:c.2312G>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.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. 15/21 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
• Publications: 8 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 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 1248 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM1	NM_001198.4	MANE Select	c.2312G>A	p.Gly771Asp	missense	Exon 7 of 7	NP_001189.2	O75626-1
	PRDM1	NM_182907.3		c.1910G>A	p.Gly637Asp	missense	Exon 5 of 5	NP_878911.1	O75626-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM1	ENST00000369096.9	TSL:1 MANE Select	c.2312G>A	p.Gly771Asp	missense	Exon 7 of 7	ENSP00000358092.4	O75626-1
	PRDM1	ENST00000369091.6	TSL:1	c.2204G>A	p.Gly735Asp	missense	Exon 7 of 7	ENSP00000358087.2	O75626-2
	PRDM1	ENST00000369089.3	TSL:1	c.1910G>A	p.Gly637Asp	missense	Exon 5 of 5	ENSP00000358085.3	O75626-3

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

GnomAD2 exomes AF: 0.00272 AC: 684 AN: 251484 AF XY: 0.00216

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 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

African (AFR) AF: 0.0274 AC: 918 AN: 33480

American (AMR) AF: 0.00389 AC: 174 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000650 AC: 17 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.000469 AC: 521 AN: 1112012

Other (OTH) AF: 0.00277 AC: 167 AN: 60396

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

African (AFR) AF: 0.0268 AC: 1114 AN: 41492

American (AMR) AF: 0.00373 AC: 57 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68008

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00371 Hom.: 11

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

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.049
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.67	N
REVEL	Benign	0.051
Sift	Benign	0.18	T
Sift4G	Benign	0.54	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
Mutation Taster		=99/1	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: rs80257572; hg19: chr6-106555195; COSMIC: COSV64844784; COSMIC: COSV64844784;