rs387906957
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_016013.4(NDUFAF1):āc.758A>Gā(p.Lys253Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,888 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 30)
Exomes š: 0.0000082 ( 0 hom. )
Consequence
NDUFAF1
NM_016013.4 missense, splice_region
NM_016013.4 missense, splice_region
Scores
1
7
11
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 3.27
Genes affected
NDUFAF1 (HGNC:18828): (NADH:ubiquinone oxidoreductase complex assembly factor 1) This gene encodes a complex I assembly factor protein. Complex I (NADH-ubiquinone oxidoreductase) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. The encoded protein is required for assembly of complex I, and mutations in this gene are a cause of mitochondrial complex I deficiency. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 19. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFAF1 | NM_016013.4 | c.758A>G | p.Lys253Arg | missense_variant, splice_region_variant | 3/5 | ENST00000260361.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFAF1 | ENST00000260361.9 | c.758A>G | p.Lys253Arg | missense_variant, splice_region_variant | 3/5 | 1 | NM_016013.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152098Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251450Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135908
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461790Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727196
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152098Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74278
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Mitochondrial complex 1 deficiency, nuclear type 11 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 11, 2007 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 14, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). ClinVar contains an entry for this variant (Variation ID: 30623). This variant is also known as c.1140A>G. This missense change has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 17557076). This variant is present in population databases (rs387906957, gnomAD 0.003%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 253 of the NDUFAF1 protein (p.Lys253Arg). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Loss of methylation at K253 (P = 0.0176);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 5
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at