Variant 1-12794282-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_023013.4(PRAMEF1):c.655C>T(p.Arg219Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000565 in 1,611,958 control chromosomes in the GnomAD database, including 31 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00067 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 29 hom. )

Consequence

PRAMEF1
NM_023013.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.43

Variant links:

Genes affected

PRAMEF1 (HGNC:28840): (PRAME family member 1) This gene is a member of the PRAME (preferentially expressed antigen of melanoma) gene family which is expressed in many cancers but may function in reproductive tissues during development. Alternative promoter usage generates two transcript variants, which encode different isoforms. [provided by RefSeq, Jun 2014]

PRAMEF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0075188577).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRAMEF1	NM_023013.4 linkuse as main transcript	c.655C>T	p.Arg219Cys	missense_variant	3/4	ENST00000332296.7	NP_075389.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRAMEF1	ENST00000332296.7 linkuse as main transcript	c.655C>T	p.Arg219Cys	missense_variant	3/4	1	NM_023013.4	ENSP00000332134	P1

Frequencies

GnomAD3 genomes

AF:

0.000667

AC:

101

AN:

151536

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000970

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00165

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00126

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000722

Gnomad OTH

AF:

0.00241

GnomAD3 exomes

AF:

0.000908

AC:

228

AN:

251038

Hom.:

AF XY:

0.00107

AC XY:

145

AN XY:

135688

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00467

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000855

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000554

AC:

809

AN:

1460302

Hom.:

Cov.:

AF XY:

0.000619

AC XY:

450

AN XY:

726458

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00108

Gnomad4 ASJ exome

AF:

0.00452

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00106

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.000418

Gnomad4 OTH exome

AF:

0.00101

GnomAD4 genome

AF:

0.000666

AC:

101

AN:

151656

Hom.:

Cov.:

AF XY:

0.000756

AC XY:

AN XY:

74100

show subpopulations

Gnomad4 AFR

AF:

0.0000967

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.00127

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000722

Gnomad4 OTH

AF:

0.00239

Alfa

AF:

0.00113

Hom.:

Bravo

AF:

0.000827

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000964

AC:

117

EpiCase

AF:

0.000982

EpiControl

AF:

0.00160

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2021

The c.655C>T (p.R219C) alteration is located in exon 3 (coding exon 2) of the PRAMEF1 gene. This alteration results from a C to T substitution at nucleotide position 655, causing the arginine (R) at amino acid position 219 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.71

CADD

Benign

4.1

DANN

Benign

0.69

DEOGEN2

Benign

0.0017

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.00060

LIST_S2

Benign

0.47

M_CAP

Benign

0.0014

MetaRNN

Benign

0.0075

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.035

MutationTaster

Benign

1.0

PrimateAI

Benign

0.46

PROVEAN

Benign

0.020

REVEL

Benign

0.0070

Sift

Benign

0.12

Sift4G

Benign

0.14

Polyphen

0.0

Vest4

0.16

MVP

0.014

MPC

0.49

ClinPred

0.0093

GERP RS

-3.2

Varity_R

0.058

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over