Genetic Variant ENST00000692152.1:c.-48-12843C>T (chr22-42649689-G-A) – 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.-48-12843C>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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.721

Publications

6 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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
CYB5R3	ENST00000692152.1 link	c.-48-12843C>T	intron_variant	Intron 1 of 8	ENSP00000509317.1
CYB5R3	ENST00000686129.1 link	c.-48-12843C>T	intron_variant	Intron 1 of 4	ENSP00000508623.1
CYB5R3	ENST00000693716.1 link	n.250-12843C>T	intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes

AF:

0.138

AC:

20989

AN:

152050

Hom.:

2061

Cov.:

show subpopulations

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:

AN:

396

Hom.:

AF XY:

0.110

AC XY:

AN XY:

308

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.167

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0901

AC:

AN:

344

Other (OTH)

AF:

0.188

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.138

AC:

21006

AN:

152166

Hom.:

2059

Cov.:

AF XY:

0.144

AC XY:

10687

AN XY:

74390

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.102

AC:

6941

AN:

67992

Other (OTH)

AF:

0.141

AC:

299

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

791

1582

2374

3165

3956

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<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:

0.123

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

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

4.4

(source)

DANN

Benign

0.94

PhyloP100

-0.72

PromoterAI

-0.050

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over