chr8-38392690-G-A

Variant summary

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

The NM_001286819.2(LETM2):​c.196G>A​(p.Val66Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

LETM2
NM_001286819.2 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0260
Variant links:
Genes affected
LETM2 (HGNC:14648): (leucine zipper and EF-hand containing transmembrane protein 2) Predicted to enable ribosome binding activity. Predicted to be involved in cellular metal ion homeostasis. Predicted to be located in mitochondrial inner membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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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=0.060481757).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LETM2NM_001286819.2 linkuse as main transcriptc.196G>A p.Val66Ile missense_variant 3/11 ENST00000379957.9 NP_001273748.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LETM2ENST00000379957.9 linkuse as main transcriptc.196G>A p.Val66Ile missense_variant 3/115 NM_001286819.2 ENSP00000369291 P4Q2VYF4-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 12, 2024The c.55G>A (p.V19I) alteration is located in exon 3 (coding exon 1) of the LETM2 gene. This alteration results from a G to A substitution at nucleotide position 55, causing the valine (V) at amino acid position 19 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
0.067
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
0.28
DANN
Benign
0.36
DEOGEN2
Benign
0.0099
.;T;.;T;T;.;T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.55
T;T;T;T;T;T;T
M_CAP
Benign
0.0031
T
MetaRNN
Benign
0.060
T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.20
.;.;.;.;N;.;.
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.36
N;N;N;N;N;N;N
REVEL
Benign
0.0090
Sift
Benign
0.23
T;T;T;T;T;T;T
Sift4G
Benign
0.32
T;T;T;T;T;T;T
Polyphen
0.0010, 0.0
.;B;.;B;B;.;.
Vest4
0.023, 0.058, 0.057, 0.032, 0.039
MutPred
0.24
Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);
MVP
0.014
MPC
0.049
ClinPred
0.079
T
GERP RS
0.41
Varity_R
0.034
gMVP
0.058

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-38250208; API