rs8190366

Positions:

• chr22-42649531-T-C
• chr22-42649531-T-G

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.-48-12685A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,320 control chromosomes in the GnomAD database, including 2,006 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1994 hom., cov: 32)
  • Exomes 𝑓: 0.16 (12 hom.)
• Consequence: CYB5R3 ENST00000692152.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.758

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 22-42649531-T-C is Benign according to our data. Variant chr22-42649531-T-C is described in ClinVar as [Benign]. Clinvar id is 1289106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000686129.1	c.-48-12685A>G		intron_variant				ENSP00000508623
CYB5R3	ENST00000692152.1	c.-48-12685A>G		intron_variant				ENSP00000509317
CYB5R3	ENST00000693716.1	n.250-12685A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20645 AN: 151626 Hom.: 1997 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0814

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.141

GnomAD4 exome AF: 0.161 AC: 93 AN: 576 Hom.: 12 Cov.: 0 AF XY: 0.169 AC XY: 61 AN XY: 360

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.0455

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.600

Gnomad4 SAS exome AF: 0.0714

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.154

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.136 AC: 20662 AN: 151744 Hom.: 1994 Cov.: 32 AF XY: 0.142 AC XY: 10502 AN XY: 74136

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.0814

Gnomad4 EAS AF: 0.581

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.139

Alfa AF: 0.129 Hom.: 178

Bravo AF: 0.132

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	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.0
DANN	Benign	0.64

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: rs8190366; hg19: chr22-43045537;