chr1-12941141-C-T

Variant summary

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

The NM_001010889.2(PRAMEF6):​c.712G>A​(p.Val238Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 2)
Exomes 𝑓: 0.00022 ( 3 hom. )
Failed GnomAD Quality Control

Consequence

PRAMEF6
NM_001010889.2 missense

Scores

1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.88
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]

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=0.07561666).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRAMEF6NM_001010889.2 linkc.712G>A p.Val238Ile 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
PRAMEF6ENST00000376189.5 linkc.712G>A p.Val238Ile missense_variant Exon 3 of 4 1 NM_001010889.2 ENSP00000365360.1 Q5VXH4
PRAMEF6ENST00000415464.6 linkc.712G>A p.Val238Ile missense_variant Exon 3 of 4 1 ENSP00000401281.2 Q5VXH4

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
3
AN:
10134
Hom.:
0
Cov.:
2
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000812
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:
0.000350
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000980
AC:
5
AN:
51004
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
25654
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000240
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.000224
AC:
87
AN:
388816
Hom.:
3
Cov.:
3
AF XY:
0.000202
AC XY:
41
AN XY:
203418
show subpopulations
Gnomad4 AFR exome
AF:
0.000381
Gnomad4 AMR exome
AF:
0.0000589
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000185
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000301
Gnomad4 OTH exome
AF:
0.000272
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.000296
AC:
3
AN:
10134
Hom.:
0
Cov.:
2
AF XY:
0.000220
AC XY:
1
AN XY:
4548
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000812
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000350
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 09, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.712G>A (p.V238I) alteration is located in exon 3 (coding exon 2) of the PRAMEF6 gene. This alteration results from a G to A substitution at nucleotide position 712, causing the valine (V) at amino acid position 238 to be replaced by an isoleucine (I). 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
0.086
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.79
CADD
Benign
0.075
DANN
Benign
0.40
DEOGEN2
Benign
0.0022
T;T
Eigen
Benign
-2.7
Eigen_PC
Benign
-2.7
FATHMM_MKL
Benign
0.00038
N
M_CAP
Benign
0.00093
T
MetaRNN
Benign
0.076
T;T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
-0.20
N;N
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
0.31
N;N
REVEL
Benign
0.018
Sift
Benign
0.51
T;T
Sift4G
Benign
0.51
T;T
Polyphen
0.0010
B;B
Vest4
0.047
MutPred
0.27
Loss of catalytic residue at V238 (P = 0.0226);Loss of catalytic residue at V238 (P = 0.0226);
MVP
0.043
MPC
1.4
ClinPred
0.052
T
GERP RS
-3.1
Varity_R
0.017
gMVP
0.12

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.

Other links and lift over

dbSNP: rs761497343; hg19: chr1-13000971; API