2-201078901-C-T
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2
The NM_002491.3(NDUFB3):c.19C>T(p.His7Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000597 in 1,610,936 control chromosomes in the GnomAD database, including 4 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
Consequence
NM_002491.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NDUFB3 | NM_002491.3 | c.19C>T | p.His7Tyr | missense_variant | Exon 2 of 3 | ENST00000237889.9 | NP_002482.1 | |
NDUFB3 | NM_001257102.2 | c.19C>T | p.His7Tyr | missense_variant | Exon 3 of 4 | NP_001244031.1 | ||
NDUFB3 | XM_011511230.4 | c.19C>T | p.His7Tyr | missense_variant | Exon 3 of 4 | XP_011509532.1 | ||
NDUFB3 | XM_047444488.1 | c.19C>T | p.His7Tyr | missense_variant | Exon 3 of 4 | XP_047300444.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000658 AC: 100AN: 151978Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000885 AC: 221AN: 249836Hom.: 1 AF XY: 0.00106 AC XY: 143AN XY: 135028
GnomAD4 exome AF: 0.000591 AC: 862AN: 1458840Hom.: 3 Cov.: 30 AF XY: 0.000701 AC XY: 509AN XY: 725748
GnomAD4 genome AF: 0.000657 AC: 100AN: 152096Hom.: 1 Cov.: 32 AF XY: 0.000673 AC XY: 50AN XY: 74342
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
p.His7Tyr (CAT>TAT): c.19 C>T in exon 2 of the NDUFB3 gene (NM_002491.2) The H7Y variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The H7Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties as Histidine are conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s). -
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The NDUFB3 p.His7Tyr variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs144513268), ClinVar (classified as a VUS by GeneDx) and LOVD 3.0. The variant was identified in control databases in 256 of 281208 chromosomes (2 homozygous) at a frequency of 0.00091 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 12 of 7168 chromosomes (freq: 0.001674), South Asian in 45 of 30172 chromosomes (freq: 0.001491), European (Finnish) in 36 of 25096 chromosomes (freq: 0.001434), European (non-Finnish) in 160 of 128586 chromosomes (freq: 0.001244), Ashkenazi Jewish in 2 of 10364 chromosomes (freq: 0.000193) and Latino in 1 of 35004 chromosomes (freq: 0.000029), while the variant was not observed in the African and East Asian populations. The p.His7 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at