rs199683937
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_007103.4(NDUFV1):c.1162+4A>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,862 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 0 hom. )
Consequence
NDUFV1
NM_007103.4 splice_donor_region, intron
NM_007103.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.4104
2
Clinical Significance
Conservation
PhyloP100: 2.43
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-67611982-A-C is Pathogenic according to our data. Variant chr11-67611982-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.53). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFV1 | NM_007103.4 | c.1162+4A>C | splice_donor_region_variant, intron_variant | ENST00000322776.11 | |||
NDUFV1 | NM_001166102.2 | c.1135+4A>C | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFV1 | ENST00000322776.11 | c.1162+4A>C | splice_donor_region_variant, intron_variant | 1 | NM_007103.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 151972Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
9
AN:
151972
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251302Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135828
GnomAD3 exomes
AF:
AC:
15
AN:
251302
Hom.:
AF XY:
AC XY:
7
AN XY:
135828
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461774Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 35AN XY: 727198
GnomAD4 exome
AF:
AC:
68
AN:
1461774
Hom.:
Cov.:
32
AF XY:
AC XY:
35
AN XY:
727198
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152088Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74358
GnomAD4 genome
?
AF:
AC:
9
AN:
152088
Hom.:
Cov.:
32
AF XY:
AC XY:
3
AN XY:
74358
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 25, 2016 | The c.1162+4A>C variant in the NDUFV1 gene has been reported previously opposite of a frameshift variant in the second NDUFV1 allele, in a patient with infantile onset intractable seizures, lactic acidemia, cerebellar ataxia, psychomotor regression, strabismus, ptosis and complex 1 deficiency confirmed in muscle and liver (Benit et al., 2001). This variant reduces the quality of the splice donor site in intron 8, and is expected to cause abnormal gene splicing. The c.1162+4A>C variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret c.1162+4A>C as a likely pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | This sequence change falls in intron 8 of the NDUFV1 gene. It does not directly change the encoded amino acid sequence of the NDUFV1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs199683937, gnomAD 0.03%). This variant has been observed in individual(s) with clinical features of mitochondrial complex I deficiency (PMID: 11349233, 26024641, 27344648, 34134969; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 1192+4A>C . ClinVar contains an entry for this variant (Variation ID: 372716). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Mitochondrial complex 1 deficiency, nuclear type 4 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2001 | - - |
Mitochondrial complex I deficiency, nuclear type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Leigh syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 06, 2021 | Variant summary: NDUFV1 c.1162+4A>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5' splicing donor site, while two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, and demonstrated exon 8 skipping (Nafisinia_2016). The variant allele was found at a frequency of 6e-05 in 251302 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NDUFV1 causing Leigh Syndrome (0.0013), allowing no conclusion about variant significance. c.1162+4A>C has been reported in the literature in multiple compound heterozygous individuals affected with Leigh Syndrome (Benit_2001, Leman_2015, Nafisinia_2016, Zhang_2021). These data indicate that the variant may be associated with disease. Some of these publications reported experimental evidence evaluating an impact on protein function, and demonstrated decreased complex I protein level, defective assembly and decreased activity in patient derived cells (e.g. Leman_2015, Nafisinia_2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic / likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at