8-38394218-A-C

Variant names:

• chr8-38394218-A-C
• rs762551516
• NM_001286819.2:c.622A>C

Variant summary

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

The NM_001286819.2(LETM2):​c.622A>C​(p.Thr208Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000194 in 1,491,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T208A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: LETM2 NM_001286819.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50
• Publications: 0 publications found

Genes affected

LETM2 (HGNC:14648): (leucine zipper and EF-hand containing transmembrane protein 2) Predicted to enable ribosome binding activity. Predicted to be involved in cellular metal ion homeostasis. Predicted to be located in mitochondrial inner membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286819.2. 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
	LETM2	NM_001286819.2	MANE Select	c.622A>C	p.Thr208Pro	missense	Exon 4 of 11	NP_001273748.1	Q2VYF4-1
	LETM2	NM_001199659.3		c.481A>C	p.Thr161Pro	missense	Exon 4 of 11	NP_001186588.1	Q2VYF4-2
	LETM2	NM_001363204.1		c.79A>C	p.Thr27Pro	missense	Exon 4 of 11	NP_001350133.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LETM2	ENST00000379957.9	TSL:5 MANE Select	c.622A>C	p.Thr208Pro	missense	Exon 4 of 11	ENSP00000369291.4	Q2VYF4-1
	LETM2	ENST00000523983.6	TSL:1	c.481A>C	p.Thr161Pro	missense	Exon 4 of 11	ENSP00000428765.2	Q2VYF4-2
	LETM2	ENST00000519476.6	TSL:1	c.*1202A>C		3_prime_UTR	Exon 3 of 3	ENSP00000429269.2	A8K1M9

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000190 AC: 2 AN: 105322 AF XY: 0.0000172

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000437

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000179 AC: 24 AN: 1338744 Hom.: 0 Cov.: 26 AF XY: 0.0000197 AC XY: 13 AN XY: 660188

African (AFR) AF: 0.00 AC: 0 AN: 29490

American (AMR) AF: 0.00 AC: 0 AN: 24436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23328

East Asian (EAS) AF: 0.00 AC: 0 AN: 35042

South Asian (SAS) AF: 0.00 AC: 0 AN: 70722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5522

European-Non Finnish (NFE) AF: 0.0000217 AC: 23 AN: 1061468

Other (OTH) AF: 0.0000179 AC: 1 AN: 55844

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74466

African (AFR) AF: 0.0000722 AC: 3 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000592 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

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	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.69		Loss of phosphorylation at T208 (P = 0.0357)
MVP		0.36
MPC		0.41
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.85
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs762551516; hg19: chr8-38251736;