5-149350983-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152407.4(GRPEL2):​c.379A>C​(p.Ile127Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GRPEL2
NM_152407.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.99
Variant links:
Genes affected
GRPEL2 (HGNC:21060): (GrpE like 2, mitochondrial) Predicted to enable adenyl-nucleotide exchange factor activity and unfolded protein binding activity. Predicted to be involved in protein import into mitochondrial matrix. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]
GRPEL2-AS1 (HGNC:48999): (GRPEL2 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.061091512).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GRPEL2NM_152407.4 linkc.379A>C p.Ile127Leu missense_variant Exon 4 of 4 ENST00000329271.8 NP_689620.2 Q8TAA5-1
GRPEL2-AS1NR_132366.1 linkn.119-2585T>G intron_variant Intron 1 of 1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GRPEL2ENST00000329271.8 linkc.379A>C p.Ile127Leu missense_variant Exon 4 of 4 1 NM_152407.4 ENSP00000329558.3 Q8TAA5-1
GRPEL2ENST00000416916.2 linkc.297A>C p.Ala99Ala synonymous_variant Exon 3 of 3 2 ENSP00000397302.2 Q8TAA5-2
GRPEL2ENST00000507562.1 linkn.509A>C non_coding_transcript_exon_variant Exon 4 of 4 3
GRPEL2-AS1ENST00000521295.1 linkn.119-2585T>G intron_variant Intron 1 of 1 3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251488
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461856
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000113
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
Oct 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.379A>C (p.I127L) alteration is located in exon 4 (coding exon 4) of the GRPEL2 gene. This alteration results from a A to C substitution at nucleotide position 379, causing the isoleucine (I) at amino acid position 127 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
0.096
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
15
DANN
Uncertain
0.97
DEOGEN2
Benign
0.057
T
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.20
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.56
T
M_CAP
Benign
0.0032
T
MetaRNN
Benign
0.061
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.69
N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-1.4
N
REVEL
Benign
0.039
Sift
Uncertain
0.013
D
Sift4G
Benign
0.12
T
Polyphen
0.047
B
Vest4
0.090
MutPred
0.43
Gain of catalytic residue at I127 (P = 0.0553);
MVP
0.38
MPC
0.22
ClinPred
0.21
T
GERP RS
3.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.11
gMVP
0.38

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: rs780855527; hg19: chr5-148730546; API