chr8-38392962-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001286819.2(LETM2):ā€‹c.468T>Gā€‹(p.His156Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,520 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

LETM2
NM_001286819.2 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.598
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29865462).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LETM2NM_001286819.2 linkuse as main transcriptc.468T>G p.His156Gln 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.468T>G p.His156Gln missense_variant 3/115 NM_001286819.2 ENSP00000369291 P4Q2VYF4-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000813
AC:
2
AN:
245996
Hom.:
0
AF XY:
0.00000750
AC XY:
1
AN XY:
133398
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000110
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:
0.00000137
AC:
2
AN:
1457520
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
725274
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
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.:
32
Bravo
AF:
0.00000378

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 GeneticsMar 21, 2023The c.327T>G (p.H109Q) alteration is located in exon 3 (coding exon 1) of the LETM2 gene. This alteration results from a T to G substitution at nucleotide position 327, causing the histidine (H) at amino acid position 109 to be replaced by a glutamine (Q). 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
0.21
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
15
DANN
Benign
0.95
DEOGEN2
Benign
0.087
T;.;T;T;.
Eigen
Benign
-0.49
Eigen_PC
Benign
-0.58
FATHMM_MKL
Benign
0.47
N
LIST_S2
Uncertain
0.88
D;D;D;T;T
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.30
T;T;T;T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
1.4
.;.;.;L;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.66
T
PROVEAN
Pathogenic
-5.0
D;D;D;D;D
REVEL
Benign
0.22
Sift
Benign
0.042
D;T;T;T;T
Sift4G
Uncertain
0.0060
D;T;T;T;T
Polyphen
1.0
D;.;D;B;.
Vest4
0.73
MutPred
0.38
Loss of catalytic residue at G157 (P = 0.1557);.;Loss of catalytic residue at G157 (P = 0.1557);Loss of catalytic residue at G157 (P = 0.1557);.;
MVP
0.040
MPC
0.089
ClinPred
0.65
D
GERP RS
-3.8
Varity_R
0.30
gMVP
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs760426573; hg19: chr8-38250480; API