Genetic Variant LETMD1:p.Arg187Gly (chr12-51055920-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_015416.5(LETMD1):c.559C>G(p.Arg187Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

LETMD1
NM_015416.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.73

Variant links:

Genes affected

LETMD1 (HGNC:24241): (LETM1 domain containing 1) This gene encodes a mitochondrial outer membrane protein. It has a potential role in tumorigenesis, which may result from negative regulation of the p53 tumor suppressor gene. Alternatively spliced transcript variants have been noted for this gene. [provided by RefSeq, Aug 2011]

LETMD1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LETMD1	NM_015416.5 link	c.559C>G	p.Arg187Gly	missense_variant	Exon 5 of 9	ENST00000262055.9	NP_056231.3	Q6P1Q0-1A0A384P5D7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LETMD1	ENST00000262055.9 link	c.559C>G	p.Arg187Gly	missense_variant	Exon 5 of 9	1	NM_015416.5	ENSP00000262055.4		Q6P1Q0-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251434

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135888

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727106

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

.;.;T;T;.;T

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D;D;D;D;D

M_CAP

Benign

0.039

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.8

.;.;M;.;.;.

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-5.1

D;D;D;D;D;D

REVEL

Uncertain

0.44

Sift

Uncertain

0.0020

D;D;D;D;D;D

Sift4G

Uncertain

0.012

D;D;D;D;D;T

Polyphen

1.0

.;.;D;D;.;D

Vest4

0.73, 0.78, 0.88, 0.72

MutPred

0.82

.;.;Gain of catalytic residue at I182 (P = 0.0019);.;.;.;

MVP

0.63

MPC

1.1

ClinPred

0.98

GERP RS

5.1

Varity_R

0.81

gMVP

0.90

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over