rs61745147

Positions:

• chr22-42623885-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PM1 PM2 BP4_Moderate BS1

The NM_000398.7(CYB5R3):​c.637G>A​(p.Glu213Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,613,984 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00074 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: CYB5R3 NM_000398.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 7.90

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM1: In a chain NADH-cytochrome b5 reductase 3 (size 299) in uniprot entity NB5R3_HUMAN there are 71 pathogenic changes around while only 8 benign (90%) in NM_000398.7
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15822002).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000742 (113/152358) while in subpopulation AFR AF= 0.00257 (107/41584). AF 95% confidence interval is 0.00218. There are 1 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYB5R3	NM_000398.7	c.637G>A	p.Glu213Lys	missense_variant	8/9	ENST00000352397.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYB5R3	ENST00000352397.10	c.637G>A	p.Glu213Lys	missense_variant	8/9	1	NM_000398.7	P3

Frequencies

GnomAD3 genomes AF: 0.000742 AC: 113 AN: 152240 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000271 AC: 68 AN: 251146 Hom.: 1 AF XY: 0.000287 AC XY: 39 AN XY: 135766

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.000173

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: 0.0000441

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000780 AC: 114 AN: 1461626 Hom.: 0 Cov.: 31 AF XY: 0.0000756 AC XY: 55 AN XY: 727120

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152358 Hom.: 1 Cov.: 33 AF XY: 0.000752 AC XY: 56 AN XY: 74500

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000191 Hom.: 0

Bravo AF: 0.00104

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

Deficiency of cytochrome-b5 reductase Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;.;.;D
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Uncertain	0.43	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.9	D;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0070	D;D;D;D;D
Sift4G	Uncertain	0.054	T;T;T;T;T
Polyphen		1.0	.;D;.;.;.
Vest4		0.93
MVP		0.95
MPC		0.17
ClinPred		0.16	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.84
gMVP		0.82

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

Other links and lift over

dbSNP: rs61745147; hg19: chr22-43019891;