NM_025207.5:c.836delT

Variant names:

• chr1-154988566-GT-G
• rs876661311
• NM_025207.5:c.836delT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_025207.5(FLAD1):​c.836delT​(p.Phe279SerfsTer45) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLAD1 NM_025207.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.56
• Publications: 2 publications found

Genes affected

FLAD1 (HGNC:24671): (flavin adenine dinucleotide synthetase 1) This gene encodes the enzyme that catalyzes adenylation of flavin mononucleotide (FMN) to form flavin adenine dinucleotide (FAD) coenzyme. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

FLAD1 Gene-Disease associations (from GenCC):

• myopathy with abnormal lipid metabolism

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 1-154988566-GT-G is Pathogenic according to our data. Variant chr1-154988566-GT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 224730.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025207.5. 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
	FLAD1	NM_025207.5	MANE Select	c.836delT	p.Phe279SerfsTer45	frameshift	Exon 2 of 7	NP_079483.3
	FLAD1	NM_201398.3		c.545delT	p.Phe182SerfsTer45	frameshift	Exon 3 of 8	NP_958800.1
	FLAD1	NM_001184891.2		c.545delT	p.Phe182SerfsTer45	frameshift	Exon 3 of 7	NP_001171820.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLAD1	ENST00000292180.8	TSL:1 MANE Select	c.836delT	p.Phe279SerfsTer45	frameshift	Exon 2 of 7	ENSP00000292180.3
	FLAD1	ENST00000315144.14	TSL:1	c.545delT	p.Phe182SerfsTer45	frameshift	Exon 3 of 8	ENSP00000317296.10
	FLAD1	ENST00000368432.5	TSL:1	c.545delT	p.Phe182SerfsTer45	frameshift	Exon 3 of 7	ENSP00000357417.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency Pathogenic:1

Mar 14, 2016

Research Unit for Molecular Medicine, Department for Clinical Medicine, Aarhus University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Myopathy with abnormal lipid metabolism Pathogenic:1

Sep 10, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs876661311; hg19: chr1-154961042;