Genetic Variant CYB5R3:c.21+3910C>T (chr22-42645385-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000398.7(CYB5R3):c.21+3910C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 152,092 control chromosomes in the GnomAD database, including 8,565 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 0.32 ( 8565 hom., cov: 32)

Consequence

CYB5R3
NM_000398.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.90

Publications

4 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 -12 ACMG points.

BP4

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

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5R3	NM_000398.7 link	c.21+3910C>T		intron_variant	Intron 1 of 8	ENST00000352397.10	NP_000389.1	P00387-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000352397.10 link	c.21+3910C>T		intron_variant	Intron 1 of 8	1	NM_000398.7	ENSP00000338461.6		P00387-1

Frequencies

GnomAD3 genomes

AF:

0.320

AC:

48694

AN:

151974

Hom.:

8550

Cov.:

show subpopulations

Gnomad AFR

AF:

0.177

Gnomad AMI

AF:

0.545

Gnomad AMR

AF:

0.383

Gnomad ASJ

AF:

0.341

Gnomad EAS

AF:

0.289

Gnomad SAS

AF:

0.450

Gnomad FIN

AF:

0.397

Gnomad MID

AF:

0.307

Gnomad NFE

AF:

0.371

Gnomad OTH

AF:

0.311

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.320

AC:

48730

AN:

152092

Hom.:

8565

Cov.:

AF XY:

0.325

AC XY:

24139

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.177

AC:

7360

AN:

41496

American (AMR)

AF:

0.383

AC:

5847

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.341

AC:

1185

AN:

3470

East Asian (EAS)

AF:

0.290

AC:

1492

AN:

5148

South Asian (SAS)

AF:

0.451

AC:

2170

AN:

4816

European-Finnish (FIN)

AF:

0.397

AC:

4202

AN:

10590

Middle Eastern (MID)

AF:

0.310

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.371

AC:

25224

AN:

67986

Other (OTH)

AF:

0.315

AC:

664

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1635

3271

4906

6542

8177

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

494

988

1482

1976

2470

<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:

0.352

Hom.:

5518

Bravo

AF:

0.312

Asia WGS

AF:

0.360

AC:

1249

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.16

(source)

DANN

Benign

0.88

PhyloP100

-1.9

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over