Genetic Variant PRAMEF6:p.Cys457Tyr (chr1-12938736-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001010889.2(PRAMEF6):c.1370G>A(p.Cys457Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 130,902 control chromosomes in the GnomAD database, including 37 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 0.11 ( 37 hom., cov: 22)

Exomes 𝑓: 0.084 ( 470 hom. )

Failed GnomAD Quality Control

Consequence

PRAMEF6
NM_001010889.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.09

Variant links:

Genes affected

PRAMEF6 (HGNC:30583): (PRAME family member 6) Enables ubiquitin ligase-substrate adaptor activity. Involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Part of Cul2-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

PRAMEF6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057281554).

BP6

Variant 1-12938736-C-T is Benign according to our data. Variant chr1-12938736-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2327228.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRAMEF6	NM_001010889.2 link	c.1370G>A	p.Cys457Tyr	missense_variant	Exon 4 of 4	ENST00000376189.5	NP_001010889.1	Q5VXH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRAMEF6	ENST00000376189.5 link	c.1370G>A	p.Cys457Tyr	missense_variant	Exon 4 of 4	1	NM_001010889.2	ENSP00000365360.1		Q5VXH4
PRAMEF6	ENST00000415464.6 link	c.1370G>A	p.Cys457Tyr	missense_variant	Exon 4 of 4	1		ENSP00000401281.2		Q5VXH4

Frequencies

GnomAD3 genomes

AF:

0.112

AC:

14685

AN:

130802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.126

Gnomad AMI

AF:

0.0370

Gnomad AMR

AF:

0.0886

Gnomad ASJ

AF:

0.0993

Gnomad EAS

AF:

0.0756

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.0665

Gnomad MID

AF:

0.0913

Gnomad NFE

AF:

0.120

Gnomad OTH

AF:

0.118

GnomAD3 exomes

AF:

0.00249

AC:

100

AN:

40140

Hom.:

AF XY:

0.00264

AC XY:

AN XY:

20480

show subpopulations

Gnomad AFR exome

AF:

0.00658

Gnomad AMR exome

AF:

0.00719

Gnomad ASJ exome

AF:

0.00616

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000234

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00159

Gnomad OTH exome

AF:

0.000707

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0836

AC:

102100

AN:

1221318

Hom.:

470

Cov.:

AF XY:

0.0857

AC XY:

52179

AN XY:

608656

show subpopulations

Gnomad4 AFR exome

AF:

0.105

Gnomad4 AMR exome

AF:

0.0564

Gnomad4 ASJ exome

AF:

0.0976

Gnomad4 EAS exome

AF:

0.0697

Gnomad4 SAS exome

AF:

0.0977

Gnomad4 FIN exome

AF:

0.0888

Gnomad4 NFE exome

AF:

0.0820

Gnomad4 OTH exome

AF:

0.0958

GnomAD4 genome

AF:

0.112

AC:

14695

AN:

130902

Hom.:

Cov.:

AF XY:

0.110

AC XY:

7017

AN XY:

64056

show subpopulations

Gnomad4 AFR

AF:

0.126

Gnomad4 AMR

AF:

0.0884

Gnomad4 ASJ

AF:

0.0993

Gnomad4 EAS

AF:

0.0754

Gnomad4 SAS

AF:

0.119

Gnomad4 FIN

AF:

0.0665

Gnomad4 NFE

AF:

0.120

Gnomad4 OTH

AF:

0.117

Alfa

AF:

0.147

Hom.:

ExAC

AF:

0.000558

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 07, 2022

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

0.054

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.12

DANN

Benign

0.28

DEOGEN2

Benign

0.0024

T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.00079

M_CAP

Benign

0.00097

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.72

N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

1.7

N;N

REVEL

Benign

0.044

Sift

Benign

0.22

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.0

B;B

Vest4

0.036

MutPred

0.38

Gain of catalytic residue at L452 (P = 0.0797);Gain of catalytic residue at L452 (P = 0.0797);

MVP

0.043

MPC

2.4

ClinPred

0.0024

GERP RS

0.17

Varity_R

0.039

gMVP

0.16

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