rs61745147
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PM1PM2BP4_ModerateBS1
The NM_000398.7(CYB5R3):c.637G>A(p.Glu213Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,613,984 control chromosomes in the GnomAD database, including 1 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
Genomes: 𝑓 0.00074 ( 1 hom., cov: 33)
Exomes 𝑓: 0.000078 ( 0 hom. )
Consequence
CYB5R3
NM_000398.7 missense
NM_000398.7 missense
Scores
4
8
5
Clinical Significance
Conservation
PhyloP100: 7.90
Genes affected
CYB5R3 (HGNC:2873): (cytochrome b5 reductase 3) This gene encodes cytochrome b5 reductase, which includes a membrane-bound form in somatic cells (anchored in the endoplasmic reticulum, mitochondrial and other membranes) and a soluble form in erythrocytes. The membrane-bound form exists mainly on the cytoplasmic side of the endoplasmic reticulum and functions in desaturation and elongation of fatty acids, in cholesterol biosynthesis, and in drug metabolism. The erythrocyte form is located in a soluble fraction of circulating erythrocytes and is involved in methemoglobin reduction. The membrane-bound form has both membrane-binding and catalytic domains, while the soluble form has only the catalytic domain. Alternate splicing results in multiple transcript variants. Mutations in this gene cause methemoglobinemias. [provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM1
?
In a chain NADH-cytochrome b5 reductase 3 (size 299) in uniprot entity NB5R3_HUMAN there are 71 pathogenic changes around while only 8 benign (90%) in NM_000398.7
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.15822002).
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000742 (113/152358) while in subpopulation AFR AF= 0.00257 (107/41584). AF 95% confidence interval is 0.00218. There are 1 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYB5R3 | NM_000398.7 | c.637G>A | p.Glu213Lys | missense_variant | 8/9 | ENST00000352397.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYB5R3 | ENST00000352397.10 | c.637G>A | p.Glu213Lys | missense_variant | 8/9 | 1 | NM_000398.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000742 AC: 113AN: 152240Hom.: 1 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.000271 AC: 68AN: 251146Hom.: 1 AF XY: 0.000287 AC XY: 39AN XY: 135766
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GnomAD4 exome AF: 0.0000780 AC: 114AN: 1461626Hom.: 0 Cov.: 31 AF XY: 0.0000756 AC XY: 55AN XY: 727120
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GnomAD4 genome ? AF: 0.000742 AC: 113AN: 152358Hom.: 1 Cov.: 33 AF XY: 0.000752 AC XY: 56AN XY: 74500
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 22, 2023 | - - |
Deficiency of cytochrome-b5 reductase Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 14, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;.;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
T;T;T;T;T
Polyphen
1.0
.;D;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at