chr9-137214206-T-C

Position:

chr9-137214206-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_014434.4(NDOR1):c.515T>C(p.Leu172Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000683 in 1,610,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

NDOR1
NM_014434.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.97

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:

NDOR1 (HGNC:):

NDOR1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36555284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDOR1	NM_014434.4 linkuse as main transcript	c.515T>C	p.Leu172Pro	missense_variant, splice_region_variant	6/14	ENST00000684003.1	NP_055249.1	Q9UHB4-1
NDOR1	NM_001144026.3 linkuse as main transcript	c.515T>C	p.Leu172Pro	missense_variant, splice_region_variant	6/14		NP_001137498.1	Q9UHB4-2
NDOR1	NM_001144028.3 linkuse as main transcript	c.515T>C	p.Leu172Pro	missense_variant, splice_region_variant	6/14		NP_001137500.1	Q9UHB4-4
NDOR1	NM_001144027.3 linkuse as main transcript	c.413T>C	p.Leu138Pro	missense_variant, splice_region_variant	5/13		NP_001137499.1	Q9UHB4-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDOR1	ENST00000684003.1 linkuse as main transcript	c.515T>C	p.Leu172Pro	missense_variant, splice_region_variant	6/14		NM_014434.4	ENSP00000507194.1		Q9UHB4-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000122

AC:

AN:

245582

Hom.:

AF XY:

0.0000225

AC XY:

AN XY:

133260

show subpopulations

Gnomad AFR exome

AF:

0.0000631

Gnomad AMR exome

AF:

0.00

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:

0.0000180

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000686

AC:

AN:

1458164

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

725382

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.515T>C (p.L172P) alteration is located in exon 6 (coding exon 6) of the NDOR1 gene. This alteration results from a T to C substitution at nucleotide position 515, causing the leucine (L) at amino acid position 172 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0045

.;.;.;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.57

T;T;T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.37

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.3

L;.;L;L

PrimateAI

Benign

0.36

PROVEAN

Benign

0.010

N;N;N;N

REVEL

Benign

0.17

Sift

Benign

0.16

T;T;T;T

Sift4G

Benign

0.31

T;T;T;T

Polyphen

0.0040

B;.;.;B

Vest4

0.59

MutPred

0.50

Gain of glycosylation at L172 (P = 0.0043);.;Gain of glycosylation at L172 (P = 0.0043);Gain of glycosylation at L172 (P = 0.0043);

MVP

0.47

MPC

0.31

ClinPred

0.31

GERP RS

2.2

Varity_R

0.094

gMVP

0.74

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