Genetic Variant PRAMEF1:p.Cys63Arg (chr1-12793414-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_023013.4(PRAMEF1):c.187T>C(p.Cys63Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,610,036 control chromosomes in the GnomAD database, including 2 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000075 ( 2 hom. )

Consequence

PRAMEF1
NM_023013.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.59

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09754929).

BP6

Variant 1-12793414-T-C is Benign according to our data. Variant chr1-12793414-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3782890.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRAMEF1	NM_023013.4 link	c.187T>C	p.Cys63Arg	missense_variant	Exon 2 of 4	ENST00000332296.7	NP_075389.2	O95521B7ZM17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRAMEF1	ENST00000332296.7 link	c.187T>C	p.Cys63Arg	missense_variant	Exon 2 of 4	1	NM_023013.4	ENSP00000332134.7		O95521

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151320

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000754

AC:

AN:

1458716

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725562

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000901

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151320

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73828

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 19, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.031

DANN

Benign

0.14

DEOGEN2

Benign

0.0055

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.00042

LIST_S2

Benign

0.036

M_CAP

Benign

0.0011

MetaRNN

Benign

0.098

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.21

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.77

REVEL

Benign

0.056

Sift

Benign

0.63

Sift4G

Benign

0.61

Polyphen

0.0

Vest4

0.11

MVP

0.014

MPC

0.64

ClinPred

0.059

GERP RS

-2.6

Varity_R

0.11

gMVP

0.26

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