chr1-12941444-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001010889.2(PRAMEF6):​c.409G>C​(p.Asp137His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,370,322 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000031 ( 1 hom., cov: 13)
Exomes 𝑓: 0.00013 ( 6 hom. )
Failed GnomAD Quality Control

Consequence

PRAMEF6
NM_001010889.2 missense

Scores

3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.96
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.061588705).
BS2
High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRAMEF6NM_001010889.2 linkc.409G>C p.Asp137His 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.409G>C p.Asp137His missense_variant Exon 3 of 4 1 NM_001010889.2 ENSP00000365360.1 Q5VXH4
PRAMEF6ENST00000415464.6 linkc.409G>C p.Asp137His missense_variant Exon 3 of 4 1 ENSP00000401281.2 Q5VXH4

Frequencies

GnomAD3 genomes
AF:
0.0000315
AC:
3
AN:
95274
Hom.:
1
Cov.:
13
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:
0.0000567
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000200
AC:
5
AN:
250562
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135550
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:
0.0000441
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000132
AC:
181
AN:
1370322
Hom.:
6
Cov.:
32
AF XY:
0.000130
AC XY:
89
AN XY:
682380
show subpopulations
Gnomad4 AFR exome
AF:
0.0000351
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:
0.00
Gnomad4 NFE exome
AF:
0.000151
Gnomad4 OTH exome
AF:
0.000375
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0000315
AC:
3
AN:
95274
Hom.:
1
Cov.:
13
AF XY:
0.00
AC XY:
0
AN XY:
45694
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:
0.0000567
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000192
Hom.:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 26, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.409G>C (p.D137H) 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 409, causing the aspartic acid (D) at amino acid position 137 to be replaced by a histidine (H). 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
0.12
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.67
CADD
Benign
0.55
DANN
Benign
0.45
DEOGEN2
Benign
0.075
T;T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.0014
N
M_CAP
Benign
0.0011
T
MetaRNN
Benign
0.062
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
L;L
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-2.7
D;D
REVEL
Benign
0.017
Sift
Uncertain
0.011
D;D
Sift4G
Benign
0.095
T;T
Polyphen
0.0060
B;B
Vest4
0.047
MutPred
0.31
Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);
MVP
0.043
MPC
1.9
ClinPred
0.045
T
GERP RS
-1.4
Varity_R
0.084
gMVP
0.27

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: rs758998491; hg19: chr1-13001274; API