4-1814424-C-G

Variant names:

• chr4-1814424-C-G
• NM_012318.3:c.2220G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_012318.3(LETM1):​c.2220G>C​(p.Ter740Tyrext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: LETM1 NM_012318.3 stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 0.443

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_012318.3 Downstream stopcodon found after 74 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LETM1	NM_012318.3	c.2220G>C	p.Ter740Tyrext*?	stop_lost	Exon 14 of 14	ENST00000302787.3	NP_036450.1
LETM1	XM_006713884.2	c.2217G>C	p.Ter739Tyrext*?	stop_lost	Exon 14 of 14		XP_006713947.1
LETM1	XM_047415673.1	c.1677G>C	p.Ter559Tyrext*?	stop_lost	Exon 13 of 13		XP_047271629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LETM1	ENST00000302787.3	c.2220G>C	p.Ter740Tyrext*?	stop_lost	Exon 14 of 14	1	NM_012318.3	ENSP00000305653.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction Pathogenic:1

Oct 25, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

LETM1-associated clinical spectrum with predominant nervous system involvement Pathogenic:1

-

Houlden Lab, UCL Institute of Neurology

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Global developmental delay Uncertain:1

Aug 01, 2021

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.0
DANN	Benign	0.76
Eigen	Benign	0.065
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.042	N
Vest4		0.046
GERP RS		0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-1816151;