Genetic Variant LETM1:p.Glu665Asp (chr4-1815739-T-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_012318.3(LETM1):c.1995A>C(p.Glu665Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000813 in 1,614,198 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0044 ( 5 hom., cov: 34)

Exomes 𝑓: 0.00044 ( 7 hom. )

Consequence

LETM1
NM_012318.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.204

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005457282).

BP6

Variant 4-1815739-T-G is Benign according to our data. Variant chr4-1815739-T-G is described in ClinVar as [Benign]. Clinvar id is 712521.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00439 (669/152328) while in subpopulation AFR AF= 0.0154 (641/41594). AF 95% confidence interval is 0.0144. There are 5 homozygotes in gnomad4. There are 319 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LETM1	NM_012318.3 link	c.1995A>C	p.Glu665Asp	missense_variant	Exon 13 of 14	ENST00000302787.3	NP_036450.1	O95202-1
LETM1	XM_006713884.2 link	c.1992A>C	p.Glu664Asp	missense_variant	Exon 13 of 14		XP_006713947.1
LETM1	XM_047415673.1 link	c.1452A>C	p.Glu484Asp	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.1995A>C	p.Glu665Asp	missense_variant	Exon 13 of 14	1	NM_012318.3	ENSP00000305653.2		O95202-1

Frequencies

GnomAD3 genomes

AF:

0.00439

AC:

668

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

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:

0.00192

GnomAD3 exomes

AF:

0.00128

AC:

323

AN:

251406

Hom.:

AF XY:

0.000890

AC XY:

121

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0172

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000441

AC:

644

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000367

AC XY:

267

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0158

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000944

GnomAD4 genome

AF:

0.00439

AC:

669

AN:

152328

Hom.:

Cov.:

AF XY:

0.00428

AC XY:

319

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0154

Gnomad4 AMR

AF:

0.00157

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:

0.00190

Alfa

AF:

0.000714

Hom.:

Bravo

AF:

0.00505

ESP6500AA

AF:

0.0159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00159

AC:

193

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.00065

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0055

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.65

REVEL

Benign

0.14

Sift

Benign

0.81

Sift4G

Benign

0.40

Polyphen

1.0

Vest4

0.50

MutPred

0.27

Loss of ubiquitination at K661 (P = 0.0962);

MVP

0.46

MPC

0.96

ClinPred

0.040

GERP RS

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.069

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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