Genetic Variant PRAME:p.Gly337Arg (chr22-22548588-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_206956.3(PRAME):c.1009G>C(p.Gly337Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PRAME
NM_206956.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.137

Variant links:

Genes affected

PRAME (HGNC:9336): (PRAME nuclear receptor transcriptional regulator) This gene encodes an antigen that is preferentially expressed in human melanomas and that is recognized by cytolytic T lymphocytes. It is not expressed in normal tissues, except testis. The encoded protein acts as a repressor of retinoic acid receptor, and likely confers a growth advantage to cancer cells via this function. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

PRAME links:

IGL (HGNC:5853):

IGL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043336183).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRAME	NM_206956.3 link	c.1009G>C	p.Gly337Arg	missense_variant	Exon 6 of 6	ENST00000405655.8	NP_996839.1	P78395A0A024R1E6B7Z986

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRAME	ENST00000405655.8 link	c.1009G>C	p.Gly337Arg	missense_variant	Exon 6 of 6	1	NM_206956.3	ENSP00000384343.3		P78395

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000805

AC:

AN:

248524

AF XY:

0.00000743

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1459688

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111858

Other (OTH)

AF:

0.0000166

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 09, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1009G>C (p.G337R) alteration is located in exon 5 (coding exon 4) of the PRAME gene. This alteration results from a G to C substitution at nucleotide position 1009, causing the glycine (G) at amino acid position 337 to be replaced by an arginine (R). 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

-0.33

BayesDel_noAF

Benign

-0.69

CADD

Benign

7.8

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.039

T;T;T;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.060

M_CAP

Benign

0.0025

MetaRNN

Benign

0.043

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.0

N;N;N;N;N

PhyloP100

0.14

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.84

N;N;N;N;N

REVEL

Benign

0.016

Sift

Benign

0.077

T;T;T;T;T

Sift4G

Benign

0.14

T;T;T;T;T

Polyphen

0.0

B;B;B;B;B

Vest4

0.11

MutPred

0.32

Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);

MVP

0.13

MPC

0.033

ClinPred

0.058

GERP RS

-1.1

Varity_R

0.067

gMVP

0.35

Mutation Taster

=99/1

polymorphism

(source)

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

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chr22-22548588-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over