Genetic Variant NDUFV2:p.Met1? (chr18-9102744-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_021074.5(NDUFV2):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000104 in 1,435,772 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: 0.000010 ( 0 hom. )

Consequence

NDUFV2
NM_021074.5 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.78

Publications

2 publications found

Variant links:

Genes affected

NDUFV2 (HGNC:7717): (NADH:ubiquinone oxidoreductase core subunit V2) The NADH-ubiquinone oxidoreductase complex (complex I) of the mitochondrial respiratory chain catalyzes the transfer of electrons from NADH to ubiquinone, and consists of at least 43 subunits. The complex is located in the inner mitochondrial membrane. This gene encodes the 24 kDa subunit of complex I, and is involved in electron transfer. Mutations in this gene are implicated in Parkinson's disease, bipolar disorder, schizophrenia, and have been found in one case of early onset hypertrophic cardiomyopathy and encephalopathy. A non-transcribed pseudogene of this locus is found on chromosome 19. [provided by RefSeq, Oct 2009]

NDUFV2 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial complex I deficiency, nuclear type 7
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial complex I deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

NDUFV2 links:

ENSG00000265257 (HGNC:):

ENSG00000265257 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 30 codons. Genomic position: 9117871. Lost 0.117 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFV2	NM_021074.5 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 8	ENST00000318388.11	NP_066552.2	P19404
NDUFV2	XR_243808.4 link	n.46A>G		non_coding_transcript_exon_variant	Exon 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFV2	ENST00000318388.11 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 8	1	NM_021074.5	ENSP00000327268.6		P19404

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

202956

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000104

AC:

AN:

1435772

Hom.:

Cov.:

AF XY:

0.00000843

AC XY:

AN XY:

712058

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32528

American (AMR)

AF:

0.00

AC:

AN:

41424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25522

East Asian (EAS)

AF:

0.0000261

AC:

AN:

38256

South Asian (SAS)

AF:

0.00

AC:

AN:

82530

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4424

European-Non Finnish (NFE)

AF:

0.0000118

AC:

AN:

1101508

Other (OTH)

AF:

0.0000169

AC:

AN:

59262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.20

LIST_S2

Uncertain

0.90

D;.

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Benign

-1.1

PhyloP100

3.8

PROVEAN

Benign

-0.26

N;.

REVEL

Benign

0.28

Sift

Benign

0.091

T;.

Sift4G

Benign

0.087

T;.

Polyphen

0.035

B;.

Vest4

0.91

MutPred

0.90

Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);

MVP

0.29

ClinPred

0.61

GERP RS

3.8

PromoterAI

-0.82

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.42

Mutation Taster

=20/180

disease causing

(source)

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

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18-9102744-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over