rs876661313

Variant names:

• chr1-154988128-CTTCT-C
• rs876661313
• NM_025207.5:c.401_404delTTCT

Variant summary

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

The NM_025207.5(FLAD1):​c.401_404delTTCT​(p.Phe134CysfsTer8) variant causes a frameshift change involving the alteration of a 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, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.61
• Publications: 5 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P

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 1-154988128-CTTCT-C is Pathogenic according to our data. Variant chr1-154988128-CTTCT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 224732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLAD1	NM_025207.5	MANE Select	c.401_404delTTCT	p.Phe134CysfsTer8	frameshift	Exon 2 of 7	NP_079483.3
	FLAD1	NM_201398.3		c.110_113delTTCT	p.Phe37CysfsTer8	frameshift	Exon 3 of 8	NP_958800.1	Q8NFF5-2
	FLAD1	NM_001184891.2		c.110_113delTTCT	p.Phe37CysfsTer8	frameshift	Exon 3 of 7	NP_001171820.1	Q8NFF5-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLAD1	ENST00000292180.8	TSL:1 MANE Select	c.401_404delTTCT	p.Phe134CysfsTer8	frameshift	Exon 2 of 7	ENSP00000292180.3	Q8NFF5-1
	FLAD1	ENST00000315144.14	TSL:1	c.110_113delTTCT	p.Phe37CysfsTer8	frameshift	Exon 3 of 8	ENSP00000317296.10	Q8NFF5-2
	FLAD1	ENST00000368432.5	TSL:1	c.110_113delTTCT	p.Phe37CysfsTer8	frameshift	Exon 3 of 7	ENSP00000357417.1	Q8NFF5-3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Myopathy with abnormal lipid metabolism (2)
1	-	-	Multiple acyl-CoA dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=0/200	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: rs876661313; hg19: chr1-154960604;