chr22-42619848-T-TG
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_000398.7(CYB5R3):c.830_831insC(p.Pro278ThrfsTer91) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,453,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
CYB5R3
NM_000398.7 frameshift
NM_000398.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.90
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 22-42619848-T-TG is Pathogenic according to our data. Variant chr22-42619848-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 1174130.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYB5R3 | NM_000398.7 | c.830_831insC | p.Pro278ThrfsTer91 | frameshift_variant | 9/9 | ENST00000352397.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYB5R3 | ENST00000352397.10 | c.830_831insC | p.Pro278ThrfsTer91 | frameshift_variant | 9/9 | 1 | NM_000398.7 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000344 AC: 5AN: 1453036Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2AN XY: 721982
GnomAD4 exome
AF:
AC:
5
AN:
1453036
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
721982
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 ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Deficiency of cytochrome-b5 reductase Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Hb Lab, Kinderklinik Ulm, University Hospital Ulm | Jun 23, 2021 | The c.830dupC duplication in CYB5R3 has been found in 2 children of 2 unrelated german families. Both children presented increased levels of methemoglobin and reduced NADH-cytochrome b5 reductase activity in blood. Sequencing of DNA from blood revealed the c.830dupC duplication and a second missense mutation (compund heterozygotes) in both children. One child presented evident symptoms of a Type II Methemoglobinemia. The second one is still beeing evaluated (june 2021). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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