Genetic Variant NDOR1:p.Arg147Leu (chr9-137213996-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014434.4(NDOR1):c.440G>T(p.Arg147Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R147P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

NDOR1
NM_014434.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.29

Publications

0 publications found

Variant links:

Genes affected

NDOR1 (HGNC:29838): (NADPH dependent diflavin oxidoreductase 1) This gene encodes an NADPH-dependent diflavin reductase that contains both flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) binding domains. The encoded protein catalyzes the transfer of electrons from NADPH through FAD and FMN cofactors to potential redox partners. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

NDOR1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014434.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDOR1	NM_014434.4	MANE Select	c.440G>T	p.Arg147Leu	missense	Exon 5 of 14	NP_055249.1	Q9UHB4-1
NDOR1	NM_001144026.3		c.440G>T	p.Arg147Leu	missense	Exon 5 of 14	NP_001137498.1	Q9UHB4-2
NDOR1	NM_001144028.3		c.440G>T	p.Arg147Leu	missense	Exon 5 of 14	NP_001137500.1	Q9UHB4-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDOR1	ENST00000684003.1	MANE Select	c.440G>T	p.Arg147Leu	missense	Exon 5 of 14	ENSP00000507194.1	Q9UHB4-1
NDOR1	ENST00000371521.8	TSL:1	c.440G>T	p.Arg147Leu	missense	Exon 5 of 14	ENSP00000360576.4	Q9UHB4-2
NDOR1	ENST00000458322.2	TSL:1	c.440G>T	p.Arg147Leu	missense	Exon 5 of 14	ENSP00000389905.1	Q9UHB4-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1402584

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

692906

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32222

American (AMR)

AF:

0.00

AC:

AN:

36248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25190

East Asian (EAS)

AF:

0.00

AC:

AN:

36688

South Asian (SAS)

AF:

0.00

AC:

AN:

80094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45450

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5404

European-Non Finnish (NFE)

AF:

9.23e-7

AC:

AN:

1083050

Other (OTH)

AF:

0.00

AC:

AN:

58238

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.043

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.027

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.77

M_CAP

Benign

0.025

MetaRNN

Benign

0.044

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.27

PhyloP100

-2.3

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.0

REVEL

Benign

0.023

Sift

Benign

0.34

Sift4G

Benign

0.31

Polyphen

0.0

Vest4

0.14

MutPred

0.39

Loss of disorder (P = 0.2106)

MVP

0.13

MPC

0.23

ClinPred

0.043

GERP RS

-2.8

Varity_R

0.16

gMVP

0.25

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.25

Position offset: -29

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over