12-51055882-A-G

Variant names:

• chr12-51055882-A-G
• rs1395110514
• NM_015416.5:c.521A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015416.5(LETMD1):​c.521A>G​(p.Lys174Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LETMD1 NM_015416.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23787528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LETMD1	NM_015416.5	c.521A>G	p.Lys174Arg	missense_variant	Exon 5 of 9	ENST00000262055.9	NP_056231.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LETMD1	ENST00000262055.9	c.521A>G	p.Lys174Arg	missense_variant	Exon 5 of 9	1	NM_015416.5	ENSP00000262055.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461734 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727164

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 Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.521A>G (p.K174R) alteration is located in exon 5 (coding exon 5) of the LETMD1 gene. This alteration results from a A to G substitution at nucleotide position 521, causing the lysine (K) at amino acid position 174 to be replaced by an arginine (R). 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	0.073
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0067	.;.;T;T;.;T
Eigen	Benign	0.030
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.77	T;T;T;T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.24	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;.;L;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.60	N;N;N;N;N;N
REVEL	Benign	0.078
Sift	Benign	0.045	D;D;T;D;T;D
Sift4G	Benign	0.24	T;T;T;T;T;T
Polyphen		0.24, 0.53, 0.17	.;.;B;P;.;B
Vest4		0.21, 0.25, 0.28, 0.21
MutPred		0.54		.;.;Gain of catalytic residue at K174 (P = 0);.;.;.;
MVP		0.22
MPC		0.24
ClinPred		0.70	D
GERP RS		5.1
Varity_R		0.10
gMVP		0.22

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

Other links and lift over

dbSNP: rs1395110514; hg19: chr12-51449665;