rs876661312

Variant names:

• chr1-154988258-GCAGGGGGCATC-CA
• rs876661312
• NM_025207.5:c.526_537delGCAGGGGGCATCinsCA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PS1 PM2 PP5_Moderate

The NM_025207.5(FLAD1):​c.526_537delGCAGGGGGCATCinsCA​(p.Ala176GlnfsTer8) variant causes a frameshift, missense 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLAD1 NM_025207.5 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.48

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS1: Transcript NM_025207.5 (FLAD1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-154988258-GCAGGGGGCATC-CA is Pathogenic according to our data. Variant chr1-154988258-GCAGGGGGCATC-CA is described in ClinVar as [Pathogenic]. Clinvar id is 224731.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLAD1	NM_025207.5	c.526_537delGCAGGGGGCATCinsCA	p.Ala176GlnfsTer8	frameshift_variant, missense_variant	Exon 2 of 7	ENST00000292180.8	NP_079483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLAD1	ENST00000292180.8	c.526_537delGCAGGGGGCATCinsCA	p.Ala176GlnfsTer8	frameshift_variant, missense_variant	Exon 2 of 7	1	NM_025207.5	ENSP00000292180.3

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

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 v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876661312; hg19: chr1-154960734;