chr22-42649452-G-T

Variant names:

• chr22-42649452-G-T
• rs8190368
• ENST00000692152.1:c.-48-12606C>A

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.-48-12606C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 156,728 control chromosomes in the GnomAD database, including 1,887 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1829 hom., cov: 32)
  • Exomes 𝑓: 0.11 (58 hom.)
• Consequence: CYB5R3 ENST00000692152.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.07
• Publications: 3 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=-0.64).
• BP6: Variant 22-42649452-G-T is Benign according to our data. Variant chr22-42649452-G-T is described in ClinVar as Benign. ClinVar VariationId is 1231332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000692152.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R3	NM_000398.7	MANE Select	c.-137C>A		upstream_gene	N/A	NP_000389.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R3	ENST00000692152.1		c.-48-12606C>A		intron	N/A	ENSP00000509317.1
	CYB5R3	ENST00000686129.1		c.-48-12606C>A		intron	N/A	ENSP00000508623.1
	CYB5R3	ENST00000693716.1		n.250-12606C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20215 AN: 149654 Hom.: 1824 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.0969

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0812

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.122

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.141

GnomAD4 exome AF: 0.108 AC: 749 AN: 6966 Hom.: 58 Cov.: 0 AF XY: 0.108 AC XY: 380 AN XY: 3526

African (AFR) AF: 0.138 AC: 16 AN: 116

American (AMR) AF: 0.0800 AC: 4 AN: 50

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 6 AN: 48

East Asian (EAS) AF: 0.500 AC: 29 AN: 58

South Asian (SAS) AF: 0.216 AC: 125 AN: 580

European-Finnish (FIN) AF: 0.242 AC: 15 AN: 62

Middle Eastern (MID) AF: 0.0833 AC: 1 AN: 12

European-Non Finnish (NFE) AF: 0.0913 AC: 531 AN: 5818

Other (OTH) AF: 0.0991 AC: 22 AN: 222

GnomAD4 genome AF: 0.135 AC: 20244 AN: 149762 Hom.: 1829 Cov.: 32 AF XY: 0.140 AC XY: 10238 AN XY: 73036

African (AFR) AF: 0.144 AC: 5923 AN: 41262

American (AMR) AF: 0.110 AC: 1660 AN: 15092

Ashkenazi Jewish (ASJ) AF: 0.0812 AC: 277 AN: 3412

East Asian (EAS) AF: 0.516 AC: 2612 AN: 5062

South Asian (SAS) AF: 0.219 AC: 1057 AN: 4828

European-Finnish (FIN) AF: 0.150 AC: 1509 AN: 10082

Middle Eastern (MID) AF: 0.128 AC: 37 AN: 290

European-Non Finnish (NFE) AF: 0.102 AC: 6785 AN: 66748

Other (OTH) AF: 0.142 AC: 296 AN: 2078

Alfa AF: 0.0608 Hom.: 68

Bravo AF: 0.131

Asia WGS AF: 0.317 AC: 1073 AN: 3400

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.93
PhyloP100		1.1
PromoterAI		-0.11	Neutral
Mutation Taster		=299/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8190368; hg19: chr22-43045458;