Genetic Variant NM_007103.4:c.3G>T (chr11-67607007-G-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_007103.4(NDUFV1):c.3G>T(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NDUFV1
NM_007103.4 start_lost

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.44

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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 18 pathogenic variants. Next in-frame start position is after 102 codons. Genomic position: 67608700. Lost 0.218 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-67607007-G-T is Pathogenic according to our data. Variant chr11-67607007-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3600152.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007103.4. 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
	NDUFV1	NM_007103.4	MANE Select	c.3G>T	p.Met1?	start_lost	Exon 1 of 10	NP_009034.2
	NDUFV1	NM_001166102.2		c.3G>T	p.Met1?	start_lost	Exon 1 of 10	NP_001159574.1	P49821-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDUFV1	ENST00000322776.11	TSL:1 MANE Select	c.3G>T	p.Met1?	start_lost	Exon 1 of 10	ENSP00000322450.6	P49821-1
NDUFV1	ENST00000529927.5	TSL:1	c.3G>T	p.Met1?	start_lost	Exon 1 of 10	ENSP00000436766.1	P49821-2
NDUFV1	ENST00000524838.5	TSL:1	n.64G>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1458690

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725482

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26036

East Asian (EAS)

AF:

0.00

AC:

AN:

39594

South Asian (SAS)

AF:

0.00

AC:

AN:

85772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111098

Other (OTH)

AF:

0.00

AC:

AN:

60224

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mitochondrial complex I deficiency, nuclear type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

Eigen

Benign

-0.090

Eigen_PC

Benign

0.030

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

-0.22

PhyloP100

4.4

PROVEAN

Benign

-0.25

REVEL

Uncertain

0.45

Sift

Uncertain

0.017

Sift4G

Uncertain

0.032

Polyphen

0.0030

Vest4

0.86

MutPred

0.91

Gain of catalytic residue at M1 (P = 0.0245)

MVP

0.89

ClinPred

1.0

GERP RS

4.3

PromoterAI

-0.019

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.76

gMVP

0.66

Mutation Taster

=22/178

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over