NM_000398.7:c.510G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM1PM2PM5BP4_Moderate

The NM_000398.7(CYB5R3):​c.510G>T​(p.Arg170Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R170G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CYB5R3
NM_000398.7 missense

Scores

4
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.502

Publications

1 publications found
Variant links:
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):
  • methemoglobinemia
    Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina
  • methemoglobinemia due to deficiency of methemoglobin reductase
    Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
  • hereditary methemoglobinemia
    Inheritance: 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.

PM1
In a chain NADH-cytochrome b5 reductase 3 (size 299) in uniprot entity NB5R3_HUMAN there are 20 pathogenic changes around while only 7 benign (74%) in NM_000398.7
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr22-42627644-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2664646.Status of the report is no_assertion_criteria_provided, 0 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.26021177).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYB5R3NM_000398.7 linkc.510G>T p.Arg170Ser missense_variant Exon 6 of 9 ENST00000352397.10 NP_000389.1 P00387-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYB5R3ENST00000352397.10 linkc.510G>T p.Arg170Ser missense_variant Exon 6 of 9 1 NM_000398.7 ENSP00000338461.6 P00387-1
ENSG00000289517ENST00000617178.5 linkn.45G>T non_coding_transcript_exon_variant Exon 1 of 14 1 ENSP00000482500.2 A0A087WZB1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461872
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727242
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000540
AC:
6
AN:
1111994
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.454
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Uncertain
0.054
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
21
DANN
Benign
0.90
DEOGEN2
Benign
0.32
.;T;.;.;.;T
Eigen
Benign
-0.41
Eigen_PC
Benign
-0.36
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.47
T;T;.;.;T;T
M_CAP
Benign
0.055
D
MetaRNN
Benign
0.24
T;T;T;T;T;T
MetaSVM
Benign
-0.48
T
MutationAssessor
Benign
1.3
.;L;.;.;.;.
PhyloP100
0.50
PrimateAI
Benign
0.32
T
PROVEAN
Uncertain
-2.7
D;D;D;D;D;D
REVEL
Benign
0.22
Sift
Benign
0.080
T;T;T;T;T;D
Sift4G
Benign
0.13
T;T;T;T;T;.
Polyphen
0.0020
.;B;.;.;.;.
Vest4
0.41
MutPred
0.41
.;Loss of MoRF binding (P = 0.0068);.;.;.;.;
MVP
0.87
MPC
0.043
ClinPred
0.68
D
GERP RS
2.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.35
gMVP
0.48
Mutation Taster
=63/37
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs61743717; hg19: chr22-43023648; API