chr12-51053802-C-T

Variant names:

• chr12-51053802-C-T
• rs145782522
• NM_015416.5:c.415C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015416.5(LETMD1):​c.415C>T​(p.Leu139Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,613,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: LETMD1 NM_015416.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.379
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12848622).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015416.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LETMD1	NM_015416.5	MANE Select	c.415C>T	p.Leu139Phe	missense	Exon 4 of 9	NP_056231.3
	LETMD1	NM_001243689.2		c.454C>T	p.Leu152Phe	missense	Exon 4 of 9	NP_001230618.1	Q6P1Q0-7
	LETMD1	NM_001351315.2		c.436C>T	p.Leu146Phe	missense	Exon 4 of 9	NP_001338244.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LETMD1	ENST00000262055.9	TSL:1 MANE Select	c.415C>T	p.Leu139Phe	missense	Exon 4 of 9	ENSP00000262055.4	Q6P1Q0-1
	LETMD1	ENST00000550929.5	TSL:1	c.247C>T	p.Leu83Phe	missense	Exon 4 of 9	ENSP00000450163.1	Q6P1Q0-2
	LETMD1	ENST00000547318.5	TSL:1	n.299C>T		non_coding_transcript_exon	Exon 3 of 8	ENSP00000448442.1	F8WCD9

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000118

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000124 AC: 31 AN: 250796 AF XY: 0.000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000873

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000691 AC: 101 AN: 1461144 Hom.: 0 Cov.: 29 AF XY: 0.0000770 AC XY: 56 AN XY: 726882

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.000112 AC: 5 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000846 AC: 94 AN: 1111658

Other (OTH) AF: 0.0000331 AC: 2 AN: 60364

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68036

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000163 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000164

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Benign	0.046
Eigen_PC	Benign	0.099
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.38
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.074
Sift	Benign	0.17	T
Sift4G	Benign	0.11	T
Polyphen		0.0090	B
Vest4		0.26
MVP		0.17
MPC		0.32
ClinPred		0.042	T
GERP RS		3.4
Varity_R		0.054
gMVP		0.44
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs145782522; hg19: chr12-51447585;