rs1057519286

chr1-29196234-A-Cchr1-29196234-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_016011.5(MECR):c.855T>G(p.Tyr285Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MECR NM_016011.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.865

Genes affected

MECR (HGNC:19691): (mitochondrial trans-2-enoyl-CoA reductase) The protein encoded by this gene is an oxidoreductase that catalyzes the last step in mitochondrial fatty acid synthesis. Defects in this gene are a cause of childhood-onset dystonia and optic atrophy. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-29196234-A-C is Pathogenic according to our data. Variant chr1-29196234-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 374879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-29196234-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECR	NM_016011.5	c.855T>G	p.Tyr285Ter	stop_gained	8/10	ENST00000263702.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECR	ENST00000263702.11	c.855T>G	p.Tyr285Ter	stop_gained	8/10	1	NM_016011.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461360 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726906

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 14, 2023	This sequence change creates a premature translational stop signal (p.Tyr285*) in the MECR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MECR are known to be pathogenic (PMID: 27817865). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dystonia (PMID: 27817865). ClinVar contains an entry for this variant (Variation ID: 374879). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	MECR: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in a patient with clinical features consistent with MECR-related disorder in published literature (Heimer et al., 2016); This variant is associated with the following publications: (PMID: 27817865) -

Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 08, 2024

- -

Optic atrophy;C0752202:Childhood Onset Dystonias Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Dec 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Benign	0.066
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.46	N
MutationTaster	Benign	1.0	A;A
Vest4		0.93
ClinPred		0.85	D
GERP RS		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: 24

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519286; hg19: chr1-29522746;