4-1815747-T-C

Variant names:

• chr4-1815747-T-C
• rs776015992
• NM_012318.3:c.1987A>G

Variant summary

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

The NM_012318.3(LETM1):​c.1987A>G​(p.Ile663Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: LETM1 NM_012318.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.72

Genes affected

LETM1 (HGNC:6556): (leucine zipper and EF-hand containing transmembrane protein 1) This gene encodes a protein that is localized to the inner mitochondrial membrane. The protein functions to maintain the mitochondrial tubular shapes and is required for normal mitochondrial morphology and cellular viability. Mutations in this gene cause Wolf-Hirschhorn syndrome, a complex malformation syndrome caused by the deletion of parts of the distal short arm of chromosome 4. Related pseudogenes have been identified on chromosomes 8, 15 and 19. [provided by RefSeq, Oct 2009]

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=0.2423932).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LETM1	NM_012318.3	c.1987A>G	p.Ile663Val	missense_variant	Exon 13 of 14	ENST00000302787.3	NP_036450.1
LETM1	XM_006713884.2	c.1984A>G	p.Ile662Val	missense_variant	Exon 13 of 14		XP_006713947.1
LETM1	XM_047415673.1	c.1444A>G	p.Ile482Val	missense_variant	Exon 12 of 13		XP_047271629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LETM1	ENST00000302787.3	c.1987A>G	p.Ile663Val	missense_variant	Exon 13 of 14	1	NM_012318.3	ENSP00000305653.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 663 of the LETM1 protein (p.Ile663Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LETM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1916623). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.00098	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.14
Sift	Benign	0.76	T
Sift4G	Benign	0.81	T
Polyphen		0.98	D
Vest4		0.39
MutPred		0.15		Gain of ubiquitination at K661 (P = 0.0804);
MVP		0.51
MPC		0.61
ClinPred		0.62	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.092
gMVP		0.30

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: rs776015992; hg19: chr4-1817474;