dbSNP rs8190368: CYB5R3:c.-48-12606C>A (chr22-42649452-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The ENST00000692152.1(CYB5R3):c.-48-12606C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 156,728 control chromosomes in the GnomAD database, including 1,887 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1829 hom., cov: 32)

Exomes 𝑓: 0.11 ( 58 hom. )

Consequence

CYB5R3
ENST00000692152.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.07

Publications

3 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: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, 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=-0.64).

BP6

Variant 22-42649452-G-T is Benign according to our data. Variant chr22-42649452-G-T is described in ClinVar as Benign. ClinVar VariationId is 1231332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.5 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.-137C>A		upstream_gene	N/A	NP_000389.1	P00387-1

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
CYB5R3	ENST00000692152.1	c.-48-12606C>A	intron	N/A	ENSP00000509317.1	P00387-2
CYB5R3	ENST00000686129.1	c.-48-12606C>A	intron	N/A	ENSP00000508623.1	A0A8I5KVD2
CYB5R3	ENST00000693716.1	n.250-12606C>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.135

AC:

20215

AN:

149654

Hom.:

1824

Cov.:

show subpopulations

Gnomad AFR

AF:

0.143

Gnomad AMI

AF:

0.0969

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.0812

Gnomad EAS

AF:

0.516

Gnomad SAS

AF:

0.219

Gnomad FIN

AF:

0.150

Gnomad MID

AF:

0.122

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.141

GnomAD4 exome

AF:

0.108

AC:

749

AN:

6966

Hom.:

Cov.:

AF XY:

0.108

AC XY:

380

AN XY:

3526

show subpopulations

African (AFR)

AF:

0.138

AC:

AN:

116

American (AMR)

AF:

0.0800

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AF:

0.216

AC:

125

AN:

580

European-Finnish (FIN)

AF:

0.242

AC:

AN:

Middle Eastern (MID)

AF:

0.0833

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0913

AC:

531

AN:

5818

Other (OTH)

AF:

0.0991

AC:

AN:

222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.135

AC:

20244

AN:

149762

Hom.:

1829

Cov.:

AF XY:

0.140

AC XY:

10238

AN XY:

73036

show subpopulations

African (AFR)

AF:

0.144

AC:

5923

AN:

41262

American (AMR)

AF:

0.110

AC:

1660

AN:

15092

Ashkenazi Jewish (ASJ)

AF:

0.0812

AC:

277

AN:

3412

East Asian (EAS)

AF:

0.516

AC:

2612

AN:

5062

South Asian (SAS)

AF:

0.219

AC:

1057

AN:

4828

European-Finnish (FIN)

AF:

0.150

AC:

1509

AN:

10082

Middle Eastern (MID)

AF:

0.128

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.102

AC:

6785

AN:

66748

Other (OTH)

AF:

0.142

AC:

296

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

814

1629

2443

3258

4072

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

232

464

696

928

1160

<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:

0.0608

Hom.:

Bravo

AF:

0.131

Asia WGS

AF:

0.317

AC:

1073

AN:

3400

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

1.1

PromoterAI

-0.11

Neutral

(source)

Mutation Taster

=299/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over