1-29216611-GGATT-G

Variant names:

• chr1-29216611-GGATT-G
• rs1057519287
• NM_016011.5:c.247_250delAATC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_016011.5(MECR):​c.247_250delAATC​(p.Asn83HisfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MECR NM_016011.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.00
• Publications: 2 publications found

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]

MECR Gene-Disease associations (from GenCC):

• dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 1-29216611-GGATT-G is Pathogenic according to our data. Variant chr1-29216611-GGATT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 374883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016011.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECR	NM_016011.5	MANE Select	c.247_250delAATC	p.Asn83HisfsTer4	frameshift	Exon 2 of 10	NP_057095.4
	MECR	NM_001349715.2		c.352_355delAATC	p.Asn118HisfsTer4	frameshift	Exon 3 of 11	NP_001336644.1
	MECR	NM_001349716.2		c.331_334delAATC	p.Asn111HisfsTer4	frameshift	Exon 3 of 11	NP_001336645.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECR	ENST00000263702.11	TSL:1 MANE Select	c.247_250delAATC	p.Asn83HisfsTer4	frameshift	Exon 2 of 10	ENSP00000263702.6
	MECR	ENST00000373791.7	TSL:2	c.19_22delAATC	p.Asn7HisfsTer4	frameshift	Exon 2 of 10	ENSP00000362896.3
	MECR	ENST00000463052.5	TSL:3	n.574_577delAATC		non_coding_transcript_exon	Exon 4 of 7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461866 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities Pathogenic:2

Kids Research, The Children's Hospital at Westmead

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Jan 08, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Nov 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asn83Hisfs*4) 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 autosomal recessive dystonia (PMID: 27817865). ClinVar contains an entry for this variant (Variation ID: 374883). For these reasons, this variant has been classified as Pathogenic.

Optic atrophy;C0752202:Childhood Onset Dystonias Pathogenic:1

Dec 01, 2016

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057519287; hg19: chr1-29543123;