rs1063796

Positions:

• chr1-12861477-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_023014.1(PRAMEF2):​c.1123T>C​(p.Cys375Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,505,846 control chromosomes in the GnomAD database, including 56,208 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.29 (6694 hom., cov: 30)
  • Exomes 𝑓: 0.25 (49514 hom.)
• Consequence: PRAMEF2 NM_023014.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.717

Genes affected

PRAMEF2 (HGNC:28841): (PRAME family member 2) Predicted to be involved in several processes, including negative regulation of apoptotic process; negative regulation of transcription, DNA-templated; and positive regulation of cell population proliferation. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014611274).
• BP6: Variant 1-12861477-T-C is Benign according to our data. Variant chr1-12861477-T-C is described in ClinVar as [Benign]. Clinvar id is 403340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRAMEF2	NM_023014.1	c.1123T>C	p.Cys375Arg	missense_variant	4/4	ENST00000240189.2	NP_075390.1
PRAMEF2	XM_011542004.1	c.388T>C	p.Cys130Arg	missense_variant	2/2		XP_011540306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRAMEF2	ENST00000240189.2	c.1123T>C	p.Cys375Arg	missense_variant	4/4	1	NM_023014.1	ENSP00000240189	P1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 39689 AN: 137696 Hom.: 6676 Cov.: 30

Gnomad AFR AF: 0.397

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.287

GnomAD4 exome AF: 0.247 AC: 338303 AN: 1368044 Hom.: 49514 Cov.: 61 AF XY: 0.246 AC XY: 167212 AN XY: 680852

Gnomad4 AFR exome AF: 0.399

Gnomad4 AMR exome AF: 0.174

Gnomad4 ASJ exome AF: 0.207

Gnomad4 EAS exome AF: 0.191

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.256

Gnomad4 NFE exome AF: 0.251

Gnomad4 OTH exome AF: 0.259

GnomAD4 genome AF: 0.288 AC: 39736 AN: 137802 Hom.: 6694 Cov.: 30 AF XY: 0.288 AC XY: 19381 AN XY: 67182

Gnomad4 AFR AF: 0.397

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.239

Gnomad4 SAS AF: 0.212

Gnomad4 FIN AF: 0.256

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.285

Alfa AF: 0.312 Hom.: 1144

ExAC AF: 0.379 AC: 45951

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.056
DANN	Benign	0.12
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.00011	N
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.2	N
MutationTaster	Benign	0.89	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	4.0	N
REVEL	Benign	0.031
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.063
ClinPred		0.00030	T
GERP RS		0.82
Varity_R		0.052
gMVP		0.22

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: rs1063796; hg19: chr1-12921332; COSMIC: COSV53571909;