rs771466122

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_025207.5(FLAD1):c.1588C>T(p.Arg530Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,614,000 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R530H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

FLAD1
NM_025207.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.41

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.882

PP5

Variant 1-154992746-C-T is Pathogenic according to our data. Variant chr1-154992746-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154992746-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLAD1	NM_025207.5 link	c.1588C>T	p.Arg530Cys	missense_variant	Exon 6 of 7	ENST00000292180.8	NP_079483.3	Q8NFF5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLAD1	ENST00000292180.8 link	c.1588C>T	p.Arg530Cys	missense_variant	Exon 6 of 7	1	NM_025207.5	ENSP00000292180.3		Q8NFF5-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251490

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000752

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Feb 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects FLAD1 function (PMID: 27259049). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 224729). This missense change has been observed in individual(s) with FLAD1-related conditions (PMID: 27259049, 31392824). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs771466122, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 530 of the FLAD1 protein (p.Arg530Cys). -

Sep 08, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R530C variant in the FLAD1 gene has previously been reported in two individuals with adult onset riboflavin responsive multiple acyl-CoA dehydrogenase deficiency who were compound heterozygous for frameshift variants in FLAD1 (Olsen et al., 2016). Functional analysis of R530C found that is is associated with higher sensitivity to proteolytic degradation and significantly reduced catalytic activity compared to wild-type (Olsen et al., 2016). The R530C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R530C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret R530C to be a pathogenic variant. -

Myopathy with abnormal lipid metabolism

Pathogenic:2

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.1588C>T, p.(Arg530Cys) is observed in exon 6 of FLAD1. This variant is observed in 39 individuals in heterozygous state in the gnomAD database. ACMG classification: Pathogenic Criteria met: PS3_Strong,PS4_Moderate, PM2_Supporting and PM3_Strong) -

Sep 10, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

- -

FLAD1-related disorder

Pathogenic:1

Feb 21, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FLAD1 c.1588C>T variant is predicted to result in the amino acid substitution p.Arg530Cys. This variant was reported in at least 3 individuals with multiple acyl-CoA dehydrogenase deficiency and multiple respiratory-chain deficiency (Olsen et al. 2016. PubMed ID: 27259049; Auranen et al. 2017. PubMed ID: 28433476; Muru et al. 2019. PubMed ID: 31392824). Functional studies suggest that the p.Arg530Cys substitution impacts the normal FLAD1protein function (Olsen et al. 2016. PubMed ID: 27259049). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-154965222-C-T). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

.;.;D;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.88

D;D;D;D

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

3.6

.;.;H;.

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.0

D;D;D;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

.;.;D;.

Vest4

0.91

MutPred

0.67

.;.;Loss of MoRF binding (P = 0.0865);.;

MVP

0.54

MPC

0.96

ClinPred

0.99

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over