Variant 8-38394218-A-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001286819.2(LETM2):c.622A>C(p.Thr208Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000194 in 1,491,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T208A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

LETM2
NM_001286819.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.50

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]

LETM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LETM2	NM_001286819.2 linkuse as main transcript	c.622A>C	p.Thr208Pro	missense_variant	4/11	ENST00000379957.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LETM2	ENST00000379957.9 linkuse as main transcript	c.622A>C	p.Thr208Pro	missense_variant	4/11	5	NM_001286819.2	P4	Q2VYF4-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000190

AC:

AN:

105322

Hom.:

AF XY:

0.0000172

AC XY:

AN XY:

58202

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000437

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1338744

Hom.:

Cov.:

AF XY:

0.0000197

AC XY:

AN XY:

660188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000217

Gnomad4 OTH exome

AF:

0.0000179

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000722

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000592

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

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 submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.481A>C (p.T161P) alteration is located in exon 4 (coding exon 2) of the LETM2 gene. This alteration results from a A to C substitution at nucleotide position 481, causing the threonine (T) at amino acid position 161 to be replaced by a proline (P). 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

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Uncertain

-0.19

MutationAssessor

Pathogenic

3.8

H;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.70

MutPred

0.69

Loss of phosphorylation at T208 (P = 0.0357);.;

MVP

0.36

MPC

0.41

ClinPred

0.98

GERP RS

4.9

Varity_R

0.90

gMVP

0.85

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over