ENST00000692152.1:c.-48-12713G>A

Variant names:

• chr22-42649559-C-T
• rs8190365
• ENST00000692152.1:c.-48-12713G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000692152.1(CYB5R3):​c.-48-12713G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 152,566 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.016 (58 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (0 hom.)
• Consequence: CYB5R3 ENST00000692152.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.459
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0527 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.-244G>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.-48-12713G>A		intron	N/A	ENSP00000509317.1
	CYB5R3	ENST00000686129.1		c.-48-12713G>A		intron	N/A	ENSP00000508623.1
	CYB5R3	ENST00000693716.1		n.250-12713G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2387 AN: 152040 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.0546

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00955

GnomAD4 exome AF: 0.00244 AC: 1 AN: 410 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 260

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

American (AMR) AF: 0.00 AC: 0 AN: 22

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 8

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 334

Other (OTH) AF: 0.00 AC: 0 AN: 20

GnomAD4 genome AF: 0.0157 AC: 2391 AN: 152156 Hom.: 58 Cov.: 32 AF XY: 0.0151 AC XY: 1123 AN XY: 74402

African (AFR) AF: 0.0545 AC: 2264 AN: 41520

American (AMR) AF: 0.00549 AC: 84 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67986

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.0149 Hom.: 6

Bravo AF: 0.0179

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.5
DANN	Benign	0.93
PhyloP100		-0.46
PromoterAI		-0.17	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: rs8190365; hg19: chr22-43045565;