rs104894705
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong
The NM_024407.5(NDUFS7):c.364G>A(p.Val122Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,613,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000086 ( 0 hom. )
Consequence
NDUFS7
NM_024407.5 missense
NM_024407.5 missense
Scores
13
3
1
Clinical Significance
Conservation
PhyloP100: 9.43
Genes affected
NDUFS7 (HGNC:7714): (NADH:ubiquinone oxidoreductase core subunit S7) This gene encodes a protein that is a subunit of one of the complexes that forms the mitochondrial respiratory chain. This protein is one of over 40 subunits found in complex I, the nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase. This complex functions in the transfer of electrons from NADH to the respiratory chain, and ubiquinone is believed to be the immediate electron acceptor for the enzyme. Mutations in this gene cause Leigh syndrome due to mitochondrial complex I deficiency, a severe neurological disorder that results in bilaterally symmetrical necrotic lesions in subcortical brain regions. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
?
In a chain NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial (size 174) in uniprot entity NDUS7_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_024407.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.839
PP5
?
Variant 19-1391006-G-A is Pathogenic according to our data. Variant chr19-1391006-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1391006-G-A is described in Lovd as [Likely_pathogenic]. Variant chr19-1391006-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFS7 | NM_024407.5 | c.364G>A | p.Val122Met | missense_variant | 5/8 | ENST00000233627.14 | |
NDUFS7 | NM_001363602.2 | c.364G>A | p.Val122Met | missense_variant | 5/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFS7 | ENST00000233627.14 | c.364G>A | p.Val122Met | missense_variant | 5/8 | 1 | NM_024407.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152220Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
12
AN:
152220
Hom.:
Cov.:
33
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: 0.0000560 AC: 14AN: 249914Hom.: 0 AF XY: 0.0000591 AC XY: 8AN XY: 135460
GnomAD3 exomes
AF:
AC:
14
AN:
249914
Hom.:
AF XY:
AC XY:
8
AN XY:
135460
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: 0.0000856 AC: 125AN: 1460992Hom.: 0 Cov.: 33 AF XY: 0.0000812 AC XY: 59AN XY: 726836
GnomAD4 exome
AF:
AC:
125
AN:
1460992
Hom.:
Cov.:
33
AF XY:
AC XY:
59
AN XY:
726836
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: 0.0000788 AC: 12AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74356
GnomAD4 genome
?
AF:
AC:
12
AN:
152220
Hom.:
Cov.:
33
AF XY:
AC XY:
6
AN XY:
74356
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
0
ALSPAC
AF:
AC:
2
ExAC
?
AF:
AC:
4
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 122 of the NDUFS7 protein (p.Val122Met). This variant is present in population databases (rs104894705, gnomAD 0.009%). This missense change has been observed in individuals with autosomal recessive Leigh syndrome (PMID: 10330338, 10360771, 30369941). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7681). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NDUFS7 function (PMID: 11004438). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 05, 2023 | In vitro functional study in yeast indicated that the V119M variant in NUKM, that corresponds to the V122M variant in NDUFS7 gene in humans, impairs complex I activity (Ahlers et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10330338, 22033105, 14749350, 29144225, 31014978, 30369941, 29977174, 10360771, 15269216, 18513682, 15576052, 36557887, 35718301, 11004438) - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Mitochondrial complex 1 deficiency, nuclear type 3 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 05, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 24, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 18, 2022 | - - |
Leigh syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 01, 2023 | Variant summary: NDUFS7 c.364G>A (p.Val122Met) results in a conservative amino acid change located in the NADH:ubiquinone oxidoreductase-like, 20kDa subunit (IPR006137) of the encoded protein sequence. The variant allele was found at a frequency of 5.6e-05 in 249914 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NDUFS7 causing Leigh Syndrome (5.6e-05 vs 0.0013), allowing no conclusion about variant significance. c.364G>A has been reported in the literature in multiple individuals affected with Complex 1 deficiency and Leigh Syndrome (examples: Triepels_1999 and Theunissen_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. V119M in NUKM protein of Y. lipolytica corresponds to V122M variant in NDUFS7 gene in humans, this variant impaired complex1 activity in vitro (Ahlers_2000). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.;.;H;.;.
MutationTaster
Benign
A;A;A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;.;D;D;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;D;D;.;D
Sift4G
Pathogenic
D;D;D;D;D;D;D
Polyphen
1.0
.;D;.;D;.;.;.
Vest4
MVP
MPC
1.4
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at