Genetic Variant NM_001286819.2:c.568A>G (chr8-38394164-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001286819.2(LETM2):c.568A>G(p.Met190Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,518,182 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000044 ( 0 hom. )

Consequence

LETM2
NM_001286819.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286819.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LETM2	NM_001286819.2	MANE Select	c.568A>G	p.Met190Val	missense	Exon 4 of 11	NP_001273748.1	Q2VYF4-1
LETM2	NM_001199659.3		c.427A>G	p.Met143Val	missense	Exon 4 of 11	NP_001186588.1	Q2VYF4-2
LETM2	NM_001363204.1		c.25A>G	p.Met9Val	missense	Exon 4 of 11	NP_001350133.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LETM2	ENST00000379957.9	TSL:5 MANE Select	c.568A>G	p.Met190Val	missense	Exon 4 of 11	ENSP00000369291.4	Q2VYF4-1
LETM2	ENST00000523983.6	TSL:1	c.427A>G	p.Met143Val	missense	Exon 4 of 11	ENSP00000428765.2	Q2VYF4-2
LETM2	ENST00000519476.6	TSL:1	c.*1148A>G		3_prime_UTR	Exon 3 of 3	ENSP00000429269.2	A8K1M9

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000478

GnomAD2 exomes

AF:

0.00000794

AC:

AN:

125878

AF XY:

0.0000146

show subpopulations

Gnomad AFR exome

AF:

0.000159

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000439

AC:

AN:

1366018

Hom.:

Cov.:

AF XY:

0.00000594

AC XY:

AN XY:

673906

show subpopulations

African (AFR)

AF:

0.000129

AC:

AN:

30922

American (AMR)

AF:

0.00

AC:

AN:

32032

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24770

East Asian (EAS)

AF:

0.00

AC:

AN:

35396

South Asian (SAS)

AF:

0.00

AC:

AN:

75092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1071456

Other (OTH)

AF:

0.0000350

AC:

AN:

57174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41438

American (AMR)

AF:

0.0000655

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000680

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

M_CAP

Benign

0.046

MetaRNN

Uncertain

0.74

MetaSVM

Benign

-0.40

MutationAssessor

Pathogenic

3.5

PhyloP100

9.3

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.49

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

0.99

Vest4

0.68

MutPred

0.72

Gain of catalytic residue at M190 (P = 0.1138)

MVP

0.32

MPC

0.36

ClinPred

0.84

GERP RS

6.0

Varity_R

0.66

gMVP

0.71

Mutation Taster

=29/71

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over