rs8190366

Variant names:

• chr22-42649531-T-C
• rs8190366
• ENST00000692152.1:c.-48-12685A>G

Your query was ambiguous. Multiple possible variants found:

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

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.-48-12685A>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
• Publications: 2 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: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, 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=-0.88).
• BP6: Variant 22-42649531-T-C is Benign according to our data. Variant chr22-42649531-T-C is described in ClinVar as Benign. ClinVar VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R3	NM_000398.7	MANE Select	c.-216A>G		upstream_gene	N/A	NP_000389.1	P00387-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R3	ENST00000692152.1		c.-48-12685A>G		intron	N/A	ENSP00000509317.1	P00387-2
	CYB5R3	ENST00000686129.1		c.-48-12685A>G		intron	N/A	ENSP00000508623.1	A0A8I5KVD2
	CYB5R3	ENST00000693716.1		n.250-12685A>G		intron	N/A

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

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AF: 0.0455 AC: 1 AN: 22

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6

East Asian (EAS) AF: 0.600 AC: 6 AN: 10

South Asian (SAS) AF: 0.0714 AC: 2 AN: 28

European-Finnish (FIN) AF: 0.375 AC: 9 AN: 24

Middle Eastern (MID) AF: 0.167 AC: 1 AN: 6

European-Non Finnish (NFE) AF: 0.154 AC: 70 AN: 454

Other (OTH) AF: 0.136 AC: 3 AN: 22

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

African (AFR) AF: 0.137 AC: 5688 AN: 41406

American (AMR) AF: 0.111 AC: 1690 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0814 AC: 282 AN: 3464

East Asian (EAS) AF: 0.581 AC: 2961 AN: 5098

South Asian (SAS) AF: 0.229 AC: 1101 AN: 4812

European-Finnish (FIN) AF: 0.151 AC: 1589 AN: 10506

Middle Eastern (MID) AF: 0.123 AC: 36 AN: 292

European-Non Finnish (NFE) AF: 0.102 AC: 6931 AN: 67868

Other (OTH) AF: 0.139 AC: 294 AN: 2108

Alfa AF: 0.129 Hom.: 178

Bravo AF: 0.132

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.0
DANN	Benign	0.64
PhyloP100		-0.76
PromoterAI		0.062	Neutral
Mutation Taster		=300/0	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: rs8190366; hg19: chr22-43045537;