chr9-137213978-C-A

Variant names:

• chr9-137213978-C-A
• rs760378842
• NM_014434.4:c.422C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014434.4(NDOR1):​c.422C>A​(p.Ala141Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: NDOR1 NM_014434.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDOR1	NM_014434.4	c.422C>A	p.Ala141Asp	missense_variant	Exon 5 of 14	ENST00000684003.1	NP_055249.1
NDOR1	NM_001144026.3	c.422C>A	p.Ala141Asp	missense_variant	Exon 5 of 14		NP_001137498.1
NDOR1	NM_001144028.3	c.422C>A	p.Ala141Asp	missense_variant	Exon 5 of 14		NP_001137500.1
NDOR1	NM_001144027.3	c.410+100C>A		intron_variant	Intron 4 of 12		NP_001137499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDOR1	ENST00000684003.1	c.422C>A	p.Ala141Asp	missense_variant	Exon 5 of 14		NM_014434.4	ENSP00000507194.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406004 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 694714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.22e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.096	.;.;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.035	D;D;D
Polyphen		0.95	P;.;B
Vest4		0.55
MutPred		0.67		Gain of disorder (P = 0.0328);Gain of disorder (P = 0.0328);Gain of disorder (P = 0.0328);
MVP		0.60
MPC		0.65
ClinPred		0.92	D
GERP RS		2.8
Varity_R		0.67
gMVP		0.64

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

Other links and lift over

dbSNP: rs760378842; hg19: chr9-140108430;