chr22-42649689-G-A

Variant names:

• chr22-42649689-G-A
• rs28365957
• ENST00000692152.1:c.-48-12843C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000692152.1(CYB5R3):​c.-48-12843C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 152,562 control chromosomes in the GnomAD database, including 2,061 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (2059 hom., cov: 32)
  • Exomes 𝑓: 0.098 (2 hom.)
• Consequence: CYB5R3 ENST00000692152.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.721
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 22-42649689-G-A is Benign according to our data. Variant chr22-42649689-G-A is described in ClinVar as Benign. ClinVar VariationId is 1226806.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.568 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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R3	ENST00000692152.1		c.-48-12843C>T		intron	N/A	ENSP00000509317.1
	CYB5R3	ENST00000686129.1		c.-48-12843C>T		intron	N/A	ENSP00000508623.1
	CYB5R3	ENST00000693716.1		n.250-12843C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20989 AN: 152050 Hom.: 2061 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0818

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.143

GnomAD4 exome AF: 0.0985 AC: 39 AN: 396 Hom.: 2 AF XY: 0.110 AC XY: 34 AN XY: 308

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AF: 0.00 AC: 0 AN: 2

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

East Asian (EAS) AF: 0.500 AC: 4 AN: 8

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

European-Finnish (FIN) AF: 0.167 AC: 1 AN: 6

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.0901 AC: 31 AN: 344

Other (OTH) AF: 0.188 AC: 3 AN: 16

GnomAD4 genome AF: 0.138 AC: 21006 AN: 152166 Hom.: 2059 Cov.: 32 AF XY: 0.144 AC XY: 10687 AN XY: 74390

African (AFR) AF: 0.143 AC: 5935 AN: 41530

American (AMR) AF: 0.111 AC: 1700 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0818 AC: 284 AN: 3472

East Asian (EAS) AF: 0.585 AC: 3005 AN: 5134

South Asian (SAS) AF: 0.228 AC: 1096 AN: 4808

European-Finnish (FIN) AF: 0.153 AC: 1621 AN: 10618

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6941 AN: 67992

Other (OTH) AF: 0.141 AC: 299 AN: 2114

Alfa AF: 0.123 Hom.: 173

Bravo AF: 0.134

Asia WGS AF: 0.351 AC: 1217 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 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	-0.85
CADD	Benign	4.4
DANN	Benign	0.94
PhyloP100		-0.72
PromoterAI		-0.050	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28365957; hg19: chr22-43045695;