chr9-137205850-G-A

Variant names:

• chr9-137205850-G-A
• rs367940263
• NM_014434.4:c.73G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014434.4(NDOR1):​c.73G>A​(p.Gly25Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000256 in 1,603,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G25C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: NDOR1 NM_014434.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88
• Publications: 2 publications found

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]

TMEM203 (HGNC:28217): (transmembrane protein 203) Involved in cellular calcium ion homeostasis. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31315178).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDOR1	NM_014434.4	MANE Select	c.73G>A	p.Gly25Ser	missense	Exon 1 of 14	NP_055249.1	Q9UHB4-1
	NDOR1	NM_001144026.3		c.73G>A	p.Gly25Ser	missense	Exon 1 of 14	NP_001137498.1	Q9UHB4-2
	NDOR1	NM_001144028.3		c.73G>A	p.Gly25Ser	missense	Exon 1 of 14	NP_001137500.1	Q9UHB4-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDOR1	ENST00000684003.1	MANE Select	c.73G>A	p.Gly25Ser	missense	Exon 1 of 14	ENSP00000507194.1	Q9UHB4-1
	NDOR1	ENST00000371521.8	TSL:1	c.73G>A	p.Gly25Ser	missense	Exon 1 of 14	ENSP00000360576.4	Q9UHB4-2
	NDOR1	ENST00000458322.2	TSL:1	c.73G>A	p.Gly25Ser	missense	Exon 1 of 14	ENSP00000389905.1	Q9UHB4-4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152258 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000173 AC: 4 AN: 231772 AF XY: 0.0000234

Gnomad AFR exome AF: 0.0000701

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000287

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000262 AC: 38 AN: 1450840 Hom.: 0 Cov.: 34 AF XY: 0.0000263 AC XY: 19 AN XY: 721960

African (AFR) AF: 0.0000299 AC: 1 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5562

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1110828

Other (OTH) AF: 0.0000665 AC: 4 AN: 60166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74396

African (AFR) AF: 0.0000241 AC: 1 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000650 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.00000835 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.084
Eigen_PC	Benign	0.036
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.94	L
PhyloP100		4.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.26
Sift	Benign	0.34	T
Sift4G	Benign	0.49	T
Polyphen		0.57	P
Vest4		0.46
MutPred		0.48		Gain of phosphorylation at G25 (P = 0.0124)
MVP		0.82
MPC		0.52
ClinPred		0.93	D
GERP RS		3.9
PromoterAI		-0.021	Neutral
Varity_R		0.85
gMVP		0.73
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs367940263; hg19: chr9-140100302;