Genetic Variant PRAMEF6:p.Val202Leu (chr1-12941249-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001010889.2(PRAMEF6):c.604G>C(p.Val202Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 5)

Exomes 𝑓: 0.000061 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

PRAMEF6
NM_001010889.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0480

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17441833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRAMEF6	NM_001010889.2 link	c.604G>C	p.Val202Leu	missense_variant	Exon 3 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.604G>C	p.Val202Leu	missense_variant	Exon 3 of 4	1	NM_001010889.2	ENSP00000365360.1		Q5VXH4
PRAMEF6	ENST00000415464.6 link	c.604G>C	p.Val202Leu	missense_variant	Exon 3 of 4	1		ENSP00000401281.2		Q5VXH4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

30164

Hom.:

Cov.:

FAILED QC

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:

0.0000532

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000612

AC:

AN:

703046

Hom.:

Cov.:

AF XY:

0.0000608

AC XY:

AN XY:

361762

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000319

Gnomad4 ASJ exome

AF:

0.00188

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000103

Gnomad4 OTH exome

AF:

0.000180

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000332

AC:

AN:

30164

Hom.:

Cov.:

AF XY:

0.0000734

AC XY:

AN XY:

13632

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:

0.0000532

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000146

Hom.:

ExAC

AF:

0.0000100

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.604G>C (p.V202L) alteration is located in exon 3 (coding exon 2) of the PRAMEF6 gene. This alteration results from a G to C substitution at nucleotide position 604, causing the valine (V) at amino acid position 202 to be replaced by a leucine (L). 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

0.22

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.0021

M_CAP

Benign

0.0010

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.3

L;L

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.035

Sift

Benign

0.11

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.99

D;D

Vest4

0.18

MutPred

0.46

Loss of MoRF binding (P = 0.1176);Loss of MoRF binding (P = 0.1176);

MVP

0.068

MPC

2.4

ClinPred

0.18

GERP RS

-1.4

Varity_R

0.10

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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