rs121965009
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000398.7(CYB5R3):c.316G>A(p.Val106Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,613,470 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
CYB5R3
NM_000398.7 missense
NM_000398.7 missense
Scores
3
10
4
Clinical Significance
Conservation
PhyloP100: 7.88
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 Uncertain_significance. Variant got 4 ACMG points.
PM1
?
In a domain FAD-binding FR-type (size 112) in uniprot entity NB5R3_HUMAN there are 37 pathogenic changes around while only 3 benign (93%) in NM_000398.7
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYB5R3 | NM_000398.7 | c.316G>A | p.Val106Met | missense_variant | 4/9 | ENST00000352397.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYB5R3 | ENST00000352397.10 | c.316G>A | p.Val106Met | missense_variant | 4/9 | 1 | NM_000398.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152212Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000281 AC: 7AN: 249368Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135092
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461140Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 726774
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GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152330Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74476
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Methemoglobinemia, type I Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2008 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 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. Experimental studies have shown that this missense change affects CYB5R3 function (PMID: 1400360). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CYB5R3 protein function. ClinVar contains an entry for this variant (Variation ID: 237). This variant is also known as Val105Met. This missense change has been observed in individual(s) with methemoglobinemia (PMID: 1400360, 3680497; Invitae). This variant is present in population databases (rs121965009, gnomAD 0.004%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 106 of the CYB5R3 protein (p.Val106Met). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;.;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N
REVEL
Pathogenic
Sift
Benign
T;T;T;T;T;T
Sift4G
Benign
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