12-51049164-C-A

Position:

• chr12-51049164-C-A

Variant summary

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

The NM_015416.5(LETMD1):​c.253C>A​(p.Leu85Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LETMD1 NM_015416.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.394

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]

ACMG classification

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	Protein	UniProt
LETMD1	NM_015416.5	c.253C>A	p.Leu85Met	missense_variant	2/9	ENST00000262055.9	NP_056231.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LETMD1	ENST00000262055.9	c.253C>A	p.Leu85Met	missense_variant	2/9	1	NM_015416.5	ENSP00000262055	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

The c.253C>A (p.L85M) alteration is located in exon 2 (coding exon 2) of the LETMD1 gene. This alteration results from a C to A substitution at nucleotide position 253, causing the leucine (L) at amino acid position 85 to be replaced by a methionine (M). 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	Benign	0.13
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	.;.;T;T;T;T;T;T;T;.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.71	T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.5	.;.;L;.;.;.;.;.;.;L;.
MutationTaster	Benign	0.95	D;D;D;D;D;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N;N;.;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.031	D;D;D;D;D;D;D;.;D;D;D
Sift4G	Uncertain	0.021	D;D;D;T;D;D;T;D;D;D;D
Polyphen		0.89, 0.85, 0.74	.;.;P;.;P;.;.;.;.;.;P
Vest4		0.31, 0.30, 0.31, 0.27
MutPred		0.56		.;.;Gain of catalytic residue at R81 (P = 0.0198);Gain of catalytic residue at R81 (P = 0.0198);Gain of catalytic residue at R81 (P = 0.0198);Gain of catalytic residue at R81 (P = 0.0198);Gain of catalytic residue at R81 (P = 0.0198);.;.;Gain of catalytic residue at R81 (P = 0.0198);Gain of catalytic residue at R81 (P = 0.0198);
MVP		0.38
MPC		0.43
ClinPred		0.78	D
GERP RS		1.6
Varity_R		0.080
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-51442947;