chr8-38392798-G-A

Variant names:

• chr8-38392798-G-A
• rs1212031824
• NM_001286819.2:c.304G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001363204.1(LETM2):​c.-363G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: LETM2 NM_001363204.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.542

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10319489).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LETM2	NM_001286819.2	c.304G>A	p.Val102Met	missense_variant	Exon 3 of 11	ENST00000379957.9	NP_001273748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LETM2	ENST00000379957.9	c.304G>A	p.Val102Met	missense_variant	Exon 3 of 11	5	NM_001286819.2	ENSP00000369291.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.163G>A (p.V55M) 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 163, causing the valine (V) at amino acid position 55 to be replaced by a methionine (M). 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	0.079
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	.;T;.;T;T;.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.82	T;T;T;T;T;T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.10	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	.;.;.;.;L;.;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N
REVEL	Benign	0.071
Sift	Uncertain	0.024	D;T;D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;T;T;D
Polyphen		0.96, 0.84, 0.95	.;D;.;P;P;.;.
Vest4		0.058, 0.12, 0.11, 0.13, 0.13
MutPred		0.10		Loss of glycosylation at S104 (P = 0.1054);Loss of glycosylation at S104 (P = 0.1054);.;Loss of glycosylation at S104 (P = 0.1054);Loss of glycosylation at S104 (P = 0.1054);.;Loss of glycosylation at S104 (P = 0.1054);
MVP		0.030
MPC		0.15
ClinPred		0.37	T
GERP RS		3.9
Varity_R		0.060
gMVP		0.18

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

Other links and lift over

dbSNP: rs1212031824; hg19: chr8-38250316;