22-42636864-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000398.7(CYB5R3):c.22-18C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,611,294 control chromosomes in the GnomAD database, including 16,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1778 hom., cov: 32)

Exomes 𝑓: 0.12 ( 15111 hom. )

Consequence

CYB5R3
NM_000398.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.336

Publications

20 publications found

Variant links:

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

CYB5R3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 22-42636864-G-T is Benign according to our data. Variant chr22-42636864-G-T is described in ClinVar as Benign. ClinVar VariationId is 256012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5R3	NM_000398.7 link	c.22-18C>A		intron_variant	Intron 1 of 8	ENST00000352397.10	NP_000389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000352397.10 link	c.22-18C>A		intron_variant	Intron 1 of 8	1	NM_000398.7	ENSP00000338461.6

Frequencies

GnomAD3 genomes

AF:

0.123

AC:

18672

AN:

152102

Hom.:

1784

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0900

Gnomad AMI

AF:

0.0987

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.0804

Gnomad EAS

AF:

0.582

Gnomad SAS

AF:

0.229

Gnomad FIN

AF:

0.153

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.133

GnomAD2 exomes

AF:

0.149

AC:

36798

AN:

246602

AF XY:

0.151

show subpopulations

Gnomad AFR exome

AF:

0.0908

Gnomad AMR exome

AF:

0.0830

Gnomad ASJ exome

AF:

0.0784

Gnomad EAS exome

AF:

0.589

Gnomad FIN exome

AF:

0.154

Gnomad NFE exome

AF:

0.103

Gnomad OTH exome

AF:

0.131

GnomAD4 exome

AF:

0.117

AC:

170561

AN:

1459074

Hom.:

15111

Cov.:

AF XY:

0.120

AC XY:

86846

AN XY:

725798

show subpopulations

African (AFR)

AF:

0.0925

AC:

3093

AN:

33448

American (AMR)

AF:

0.0851

AC:

3791

AN:

44568

Ashkenazi Jewish (ASJ)

AF:

0.0815

AC:

2129

AN:

26114

East Asian (EAS)

AF:

0.564

AC:

22322

AN:

39544

South Asian (SAS)

AF:

0.189

AC:

16299

AN:

86116

European-Finnish (FIN)

AF:

0.156

AC:

8095

AN:

51982

Middle Eastern (MID)

AF:

0.0951

AC:

548

AN:

5764

European-Non Finnish (NFE)

AF:

0.0955

AC:

106172

AN:

1111228

Other (OTH)

AF:

0.135

AC:

8112

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

8086

16171

24257

32342

40428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4062

8124

12186

16248

20310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.123

AC:

18680

AN:

152220

Hom.:

1778

Cov.:

AF XY:

0.129

AC XY:

9601

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0902

AC:

3747

AN:

41564

American (AMR)

AF:

0.104

AC:

1593

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0804

AC:

279

AN:

3468

East Asian (EAS)

AF:

0.581

AC:

2995

AN:

5152

South Asian (SAS)

AF:

0.229

AC:

1104

AN:

4824

European-Finnish (FIN)

AF:

0.153

AC:

1620

AN:

10598

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.102

AC:

6938

AN:

68006

Other (OTH)

AF:

0.132

AC:

278

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

791

1583

2374

3166

3957

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

220

440

660

880

1100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.109

Hom.:

1140

Bravo

AF:

0.116

Asia WGS

AF:

0.345

AC:

1197

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 12, 2018

GeneDx

Significance:Benign