chr8-38392831-A-T

Variant names:

• chr8-38392831-A-T
• rs768939911
• NM_001286819.2:c.337A>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001363204.1(LETM2):​c.-330A>T 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 0.00000274 in 1,461,826 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LETM2 NM_001363204.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.497

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 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=0.050178707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LETM2	NM_001286819.2	c.337A>T	p.Met113Leu	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.337A>T	p.Met113Leu	missense_variant	Exon 3 of 11	5	NM_001286819.2	ENSP00000369291.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.196A>T (p.M66L) alteration is located in exon 3 (coding exon 1) of the LETM2 gene. This alteration results from a A to T substitution at nucleotide position 196, causing the methionine (M) at amino acid position 66 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	0.086
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.0050
DANN	Benign	0.44
DEOGEN2	Benign	0.013	.;T;.;T;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.27	T;T;T;T;T;T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.050	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	.;.;.;.;L;.;.
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.78	N;N;N;N;N;N;N
REVEL	Benign	0.035
Sift	Benign	0.030	D;T;T;T;T;T;D
Sift4G	Uncertain	0.037	D;T;T;T;T;T;T
Polyphen		0.0030, 0.0	.;B;.;B;B;.;.
Vest4		0.048, 0.10, 0.092, 0.065, 0.081
MutPred		0.17		Gain of catalytic residue at M113 (P = 0.0444);Gain of catalytic residue at M113 (P = 0.0444);.;Gain of catalytic residue at M113 (P = 0.0444);Gain of catalytic residue at M113 (P = 0.0444);.;Gain of catalytic residue at M113 (P = 0.0444);
MVP		0.014
MPC		0.054
ClinPred		0.037	T
GERP RS		-3.7
Varity_R		0.14
gMVP		0.15

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: rs768939911; hg19: chr8-38250349;