22-42619873-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP4

The NM_000398.7(CYB5R3):c.806C>T(p.Pro269Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000871 in 1,608,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P269T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

CYB5R3
NM_000398.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 3.37

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a chain NADH-cytochrome b5 reductase 3 (size 299) in uniprot entity NB5R3_HUMAN there are 70 pathogenic changes around while only 8 benign (90%) in NM_000398.7

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-42619873-G-A is Pathogenic according to our data. Variant chr22-42619873-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 989273.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr22-42619873-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.31579065).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYB5R3	NM_000398.7 linkuse as main transcript	c.806C>T	p.Pro269Leu	missense_variant	9/9	ENST00000352397.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYB5R3	ENST00000352397.10 linkuse as main transcript	c.806C>T	p.Pro269Leu	missense_variant	9/9	1	NM_000398.7	P3	P00387-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000168

AC:

AN:

238260

Hom.:

AF XY:

0.0000233

AC XY:

AN XY:

129024

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000824

AC:

AN:

1456032

Hom.:

Cov.:

AF XY:

0.00000691

AC XY:

AN XY:

723740

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.000136

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of cytochrome-b5 reductase

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 18, 2019

The CYB5R3 c.806C>T (p.Pro269Leu) variant is a missense variant that has been reported in two studies, in which it is found in a total of 59 individuals with congenital methemoglobinemia type I, including at least in 16 in a homozygous state (Puzyrev and Maximova 2008; Burtseva et al. 2017). The p.Pro269Leu is a founder variant in the Yakut population with a frequency of heterozygous carriers of about 1% in the entire population of the Republic of Sakha and 7% in the indigenous Yakut population (Galeeva et al. 2013; Burtseva et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000119 in the Latino population of the Genome Aggregation Database. Based on the collective evidence and application of the ACMG criteria, the p.Pro269Leu variant is classified as likely pathogenic for congenital methemoglobinemia. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 989273). This variant has not been reported in the literature in individuals affected with CYB5R3-related conditions. This variant is present in population databases (rs754251915, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 269 of the CYB5R3 protein (p.Pro269Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Uncertain

0.010

Cadd

Uncertain

Dann

Uncertain

0.99

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.82

T;T;.;.;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.32

T;T;T;T;T

MetaSVM

Benign

-0.66

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.67

N;N;N;N;N

REVEL

Uncertain

0.54

Sift

Uncertain

0.012

D;D;D;D;D

Sift4G

Uncertain

0.035

D;D;D;D;D

Polyphen

0.066

.;B;.;.;.

Vest4

0.35

MutPred

0.80

.;Loss of disorder (P = 0.0154);.;.;.;

MVP

0.91

MPC

0.044

ClinPred

0.23

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.37

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over