1-154983897-A-G

Position:

chr1-154983897-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_025207.5(FLAD1):c.203A>G(p.Asp68Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000365 in 1,612,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

FLAD1
NM_025207.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.706

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:

FLAD1 (HGNC:):

FLAD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02721703).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000243 (37/152162) while in subpopulation NFE AF= 0.000441 (30/67982). AF 95% confidence interval is 0.000317. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLAD1	NM_025207.5 linkuse as main transcript	c.203A>G	p.Asp68Gly	missense_variant	1/7	ENST00000292180.8	NP_079483.3	Q8NFF5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLAD1	ENST00000292180.8 linkuse as main transcript	c.203A>G	p.Asp68Gly	missense_variant	1/7	1	NM_025207.5	ENSP00000292180.3		Q8NFF5-1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000240

AC:

AN:

250134

Hom.:

AF XY:

0.000237

AC XY:

AN XY:

135222

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000640

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000301

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000378

AC:

552

AN:

1460788

Hom.:

Cov.:

AF XY:

0.000366

AC XY:

266

AN XY:

726666

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.000875

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000438

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000243

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000267

Hom.:

Bravo

AF:

0.000329

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000231

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 06, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 68 of the FLAD1 protein (p.Asp68Gly). This variant is present in population databases (rs150060495, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with FLAD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1343852). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0058

T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.0077

MetaRNN

Benign

0.027

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

.;L

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.040

N;N

REVEL

Benign

0.21

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.014

D;D

Polyphen

0.0020

.;B

Vest4

0.14

MVP

0.35

MPC

0.34

ClinPred

0.098

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.28

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

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