12-51056243-G-C

Variant names:

• chr12-51056243-G-C
• NM_015416.5:c.760G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015416.5(LETMD1):​c.760G>C​(p.Val254Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LETMD1 NM_015416.5 missense, splice_region
• Scores: Splicing: ADA: 0.00002065
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.321

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045925736).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LETMD1	NM_015416.5	c.760G>C	p.Val254Leu	missense_variant, splice_region_variant	Exon 6 of 9	ENST00000262055.9	NP_056231.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LETMD1	ENST00000262055.9	c.760G>C	p.Val254Leu	missense_variant, splice_region_variant	Exon 6 of 9	1	NM_015416.5	ENSP00000262055.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461806 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727216

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.9
DANN	Benign	0.51
DEOGEN2	Benign	0.0039	.;.;T;T;T;T;T;T;.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.17	T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.046	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.55	.;.;N;.;.;.;.;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.070	N;N;N;N;N;N;.;N;N;N
REVEL	Benign	0.082
Sift	Benign	0.79	T;T;T;T;T;T;.;T;T;T
Sift4G	Benign	0.41	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.0010	.;.;B;B;.;.;.;.;.;B
Vest4		0.17, 0.17, 0.20, 0.18
MutPred		0.47		.;.;Gain of catalytic residue at K255 (P = 0.1242);.;.;.;.;.;.;.;
MVP		0.33
MPC		0.28
ClinPred		0.026	T
GERP RS		-4.3
Varity_R		0.022
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.010
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.

Other links and lift over

hg19: chr12-51450026;