rs121965012
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5
The NM_000398.7(CYB5R3):c.895_897delTTC(p.Phe299del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,300 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: 7.0e-7 ( 0 hom. )
Consequence
CYB5R3
NM_000398.7 conservative_inframe_deletion
NM_000398.7 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.03
Publications
4 publications found
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]
CYB5R3 Gene-Disease associations (from GenCC):
- methemoglobinemiaInheritance: AR Classification: DEFINITIVE Submitted by: Illumina
- methemoglobinemia due to deficiency of methemoglobin reductaseInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
- hereditary methemoglobinemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000398.7. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 22-42619781-CGAA-C is Pathogenic according to our data. Variant chr22-42619781-CGAA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 243.Status of the report is no_assertion_criteria_provided, 0 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000398.7. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CYB5R3 | NM_000398.7 | MANE Select | c.895_897delTTC | p.Phe299del | conservative_inframe_deletion | Exon 9 of 9 | NP_000389.1 | P00387-1 | |
| CYB5R3 | NM_001171660.2 | c.994_996delTTC | p.Phe332del | conservative_inframe_deletion | Exon 9 of 9 | NP_001165131.1 | P00387-3 | ||
| CYB5R3 | NM_001129819.2 | c.826_828delTTC | p.Phe276del | conservative_inframe_deletion | Exon 9 of 9 | NP_001123291.1 | P00387-2 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CYB5R3 | ENST00000352397.10 | TSL:1 MANE Select | c.895_897delTTC | p.Phe299del | conservative_inframe_deletion | Exon 9 of 9 | ENSP00000338461.6 | P00387-1 | |
| CYB5R3 | ENST00000407332.6 | TSL:1 | c.913_915delTTC | p.Phe305del | conservative_inframe_deletion | Exon 9 of 9 | ENSP00000384457.2 | A0A8J8Z3C6 | |
| CYB5R3 | ENST00000470741.1 | TSL:1 | n.3029_3031delTTC | non_coding_transcript_exon | Exon 6 of 6 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.99e-7 AC: 1AN: 1430300Hom.: 0 AF XY: 0.00000141 AC XY: 1AN XY: 708650 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1430300
Hom.:
AF XY:
AC XY:
1
AN XY:
708650
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33212
American (AMR)
AF:
AC:
0
AN:
39526
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25448
East Asian (EAS)
AF:
AC:
1
AN:
38656
South Asian (SAS)
AF:
AC:
0
AN:
82352
European-Finnish (FIN)
AF:
AC:
0
AN:
46710
Middle Eastern (MID)
AF:
AC:
0
AN:
5722
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1099282
Other (OTH)
AF:
AC:
0
AN:
59392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
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2
0.00
0.20
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0.60
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
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10
<30
30-35
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>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:no assertion criteria provided
Pathogenic
VUS
Benign
Condition
1
-
-
METHEMOGLOBINEMIA, TYPE II (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
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
Publications
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