dbSNP rs5996205: CYB5R3:c.-48-12855C>A (chr22-42649701-G-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The ENST00000692152.1(CYB5R3):c.-48-12855C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 152,410 control chromosomes in the GnomAD database, including 28,637 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.61 ( 28569 hom., cov: 33)

Exomes 𝑓: 0.59 ( 68 hom. )

Consequence

CYB5R3
ENST00000692152.1 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.893

Publications

7 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 22-42649701-G-T is Benign according to our data. Variant chr22-42649701-G-T is described in ClinVar as Benign. ClinVar VariationId is 1233335.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.852 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
CYB5R3	ENST00000692152.1	c.-48-12855C>A	intron	N/A	ENSP00000509317.1	P00387-2
CYB5R3	ENST00000686129.1	c.-48-12855C>A	intron	N/A	ENSP00000508623.1	A0A8I5KVD2
CYB5R3	ENST00000693716.1	n.250-12855C>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.610

AC:

92657

AN:

151940

Hom.:

28540

Cov.:

show subpopulations

Gnomad AFR

AF:

0.556

Gnomad AMI

AF:

0.881

Gnomad AMR

AF:

0.614

Gnomad ASJ

AF:

0.592

Gnomad EAS

AF:

0.873

Gnomad SAS

AF:

0.701

Gnomad FIN

AF:

0.668

Gnomad MID

AF:

0.604

Gnomad NFE

AF:

0.604

Gnomad OTH

AF:

0.606

GnomAD4 exome

AF:

0.591

AC:

208

AN:

352

Hom.:

AF XY:

0.585

AC XY:

159

AN XY:

272

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.750

AC:

AN:

South Asian (SAS)

AF:

0.667

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.597

AC:

184

AN:

308

Other (OTH)

AF:

0.550

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.610

AC:

92740

AN:

152058

Hom.:

28569

Cov.:

AF XY:

0.616

AC XY:

45786

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.556

AC:

23066

AN:

41482

American (AMR)

AF:

0.615

AC:

9398

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.592

AC:

2053

AN:

3470

East Asian (EAS)

AF:

0.873

AC:

4480

AN:

5132

South Asian (SAS)

AF:

0.701

AC:

3385

AN:

4826

European-Finnish (FIN)

AF:

0.668

AC:

7068

AN:

10578

Middle Eastern (MID)

AF:

0.612

AC:

180

AN:

294

European-Non Finnish (NFE)

AF:

0.604

AC:

41025

AN:

67962

Other (OTH)

AF:

0.607

AC:

1283

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1821

3641

5462

7282

9103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

766

1532

2298

3064

3830

<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:

0.497

Hom.:

1385

Bravo

AF:

0.604

Asia WGS

AF:

0.742

AC:

2582

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

5.7

(source)

DANN

Benign

0.87

PhyloP100

0.89

PromoterAI

0.042

Neutral

(source)

Splicing

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