22-42649452-G-T

Position:

• chr22-42649452-G-T

Variant summary

Our verdict is Benign. Variant got -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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.42649452G>T		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000692152.1	c.-48-12606C>A		intron_variant				ENSP00000509317.1
CYB5R3	ENST00000686129.1	c.-48-12606C>A		intron_variant				ENSP00000508623.1
CYB5R3	ENST00000693716.1	n.250-12606C>A		intron_variant

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

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.0800

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.216

Gnomad4 FIN exome AF: 0.242

Gnomad4 NFE exome AF: 0.0913

Gnomad4 OTH exome AF: 0.0991

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

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.0812

Gnomad4 EAS AF: 0.516

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.150

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.142

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.93

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: rs8190368; hg19: chr22-43045458;