Genetic Variant NDUFV1:c.-74T>C (chr11-67606931-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000532303.5(NDUFV1):c.-294T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,509,580 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0067 ( 11 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 11 hom. )

Consequence

NDUFV1
ENST00000532303.5 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.344

Publications

0 publications found

Variant links:

Genes affected

NDUFV1 (HGNC:7716): (NADH:ubiquinone oxidoreductase core subunit V1) The mitochondrial respiratory chain provides energy to cells via oxidative phosphorylation and consists of four membrane-bound electron-transporting protein complexes (I-IV) and an ATP synthase (complex V). This gene encodes a 51 kDa subunit of the NADH:ubiquinone oxidoreductase complex I; a large complex with at least 45 nuclear and mitochondrial encoded subunits that liberates electrons from NADH and channels them to ubiquinone. This subunit carries the NADH-binding site as well as flavin mononucleotide (FMN)- and Fe-S-biding sites. Defects in complex I are a common cause of mitochondrial dysfunction; a syndrome that occurs in approximately 1 in 10,000 live births. Mitochondrial complex I deficiency is linked to myopathies, encephalomyopathies, and neurodegenerative disorders such as Parkinson's disease and Leigh syndrome. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Oct 2009]

NDUFV1 links:

NDUFV1-DT (HGNC:26915): (NDUFV1 divergent transcript)

NDUFV1-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 11-67606931-T-C is Benign according to our data. Variant chr11-67606931-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 877316.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00673 (1024/152188) while in subpopulation AFR AF = 0.0232 (965/41534). AF 95% confidence interval is 0.022. There are 11 homozygotes in GnomAd4. There are 489 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000532303.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NDUFV1	NM_007103.4	MANE Select	c.-74T>C	upstream_gene	N/A	NP_009034.2
NDUFV1	NM_001166102.2		c.-74T>C	upstream_gene	N/A	NP_001159574.1	P49821-2
NDUFV1-DT	NR_130935.1		n.-225A>G	upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
NDUFV1	ENST00000647561.1	c.-74T>C	5_prime_UTR	Exon 2 of 11	ENSP00000497587.1	P49821-1
NDUFV1	ENST00000926237.1	c.-74T>C	5_prime_UTR	Exon 1 of 10	ENSP00000596296.1
NDUFV1	ENST00000926238.1	c.-74T>C	5_prime_UTR	Exon 1 of 10	ENSP00000596297.1

Frequencies

GnomAD3 genomes

AF:

0.00672

AC:

1022

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0233

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00336

GnomAD4 exome

AF:

0.000690

AC:

936

AN:

1357392

Hom.:

Cov.:

AF XY:

0.000615

AC XY:

414

AN XY:

673626

show subpopulations

African (AFR)

AF:

0.0219

AC:

687

AN:

31342

American (AMR)

AF:

0.00139

AC:

AN:

36564

Ashkenazi Jewish (ASJ)

AF:

0.0000401

AC:

AN:

24910

East Asian (EAS)

AF:

0.0000271

AC:

AN:

36836

South Asian (SAS)

AF:

0.000971

AC:

AN:

79278

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48216

Middle Eastern (MID)

AF:

0.000539

AC:

AN:

5566

European-Non Finnish (NFE)

AF:

0.0000299

AC:

AN:

1038018

Other (OTH)

AF:

0.00150

AC:

AN:

56662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

107

161

214

268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00673

AC:

1024

AN:

152188

Hom.:

Cov.:

AF XY:

0.00657

AC XY:

489

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0232

AC:

965

AN:

41534

American (AMR)

AF:

0.00314

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68008

Other (OTH)

AF:

0.00332

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

110

164

219

274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00485

Hom.:

Bravo

AF:

0.00769

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leigh syndrome (1)

Mitochondrial complex I deficiency, nuclear type 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Benign

0.63

PhyloP100

0.34

PromoterAI

0.063

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over