Genetic Variant NM_012318.3:c.2029G>A (chr4-1815705-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

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

The NM_012318.3(LETM1):c.2029G>A(p.Glu677Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

LETM1
NM_012318.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.45

Variant links:

Genes affected

LETM1 (HGNC:6556): (leucine zipper and EF-hand containing transmembrane protein 1) This gene encodes a protein that is localized to the inner mitochondrial membrane. The protein functions to maintain the mitochondrial tubular shapes and is required for normal mitochondrial morphology and cellular viability. Mutations in this gene cause Wolf-Hirschhorn syndrome, a complex malformation syndrome caused by the deletion of parts of the distal short arm of chromosome 4. Related pseudogenes have been identified on chromosomes 8, 15 and 19. [provided by RefSeq, Oct 2009]

LETM1 links:

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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=0.31400314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LETM1	NM_012318.3 link	c.2029G>A	p.Glu677Lys	missense_variant	Exon 13 of 14	ENST00000302787.3	NP_036450.1	O95202-1
LETM1	XM_006713884.2 link	c.2026G>A	p.Glu676Lys	missense_variant	Exon 13 of 14		XP_006713947.1
LETM1	XM_047415673.1 link	c.1486G>A	p.Glu496Lys	missense_variant	Exon 12 of 13		XP_047271629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LETM1	ENST00000302787.3 link	c.2029G>A	p.Glu677Lys	missense_variant	Exon 13 of 14	1	NM_012318.3	ENSP00000305653.2		O95202-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727236

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:

0.0000207

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 677 of the LETM1 protein (p.Glu677Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LETM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1473121). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

Eigen

Benign

0.050

Eigen_PC

Benign

0.081

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.0058

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.3

REVEL

Benign

0.043

Sift

Benign

0.17

Sift4G

Benign

0.10

Polyphen

0.79

Vest4

0.44

MutPred

0.24

Gain of ubiquitination at E677 (P = 0.0258);

MVP

0.69

MPC

0.50

ClinPred

0.88

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.45

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over