22-42649637-C-G

Variant names:

• chr22-42649637-C-G
• rs28365958
• ENST00000692152.1:c.-48-12791G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000692152.1(CYB5R3):​c.-48-12791G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 152,378 control chromosomes in the GnomAD database, including 2,039 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2037 hom., cov: 32)
  • Exomes 𝑓: 0.13 (2 hom.)
• Consequence: CYB5R3 ENST00000692152.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0790
• Publications: 6 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):

• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 22-42649637-C-G is Benign according to our data. Variant chr22-42649637-C-G is described in ClinVar as Benign. ClinVar VariationId is 1287070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5R3	NM_000398.7	c.-322G>C		upstream_gene_variant		ENST00000352397.10	NP_000389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000352397.10	c.-322G>C		upstream_gene_variant		1	NM_000398.7	ENSP00000338461.6

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20929 AN: 152030 Hom.: 2039 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0816

Gnomad EAS AF: 0.580

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.143

GnomAD4 exome AF: 0.126 AC: 29 AN: 230 Hom.: 2 AF XY: 0.156 AC XY: 25 AN XY: 160

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.100 AC: 1 AN: 10

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 2 AN: 4

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.131 AC: 26 AN: 198

Other (OTH) AF: 0.00 AC: 0 AN: 12

GnomAD4 genome AF: 0.138 AC: 20946 AN: 152148 Hom.: 2037 Cov.: 32 AF XY: 0.143 AC XY: 10648 AN XY: 74360

African (AFR) AF: 0.143 AC: 5939 AN: 41534

American (AMR) AF: 0.111 AC: 1696 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0816 AC: 283 AN: 3468

East Asian (EAS) AF: 0.579 AC: 2961 AN: 5112

South Asian (SAS) AF: 0.228 AC: 1098 AN: 4820

European-Finnish (FIN) AF: 0.152 AC: 1612 AN: 10594

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6931 AN: 67990

Other (OTH) AF: 0.141 AC: 299 AN: 2114

Alfa AF: 0.0702 Hom.: 79

Bravo AF: 0.134

Asia WGS AF: 0.348 AC: 1208 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.7
DANN	Benign	0.53
PhyloP100		-0.079
PromoterAI		-0.25	Neutral

Splicing

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

Other links and lift over

dbSNP: rs28365958; hg19: chr22-43045643;