Variant 22-42649289-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000352397.10(CYB5R3):c.21+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00342 in 1,003,646 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 59 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 29 hom. )

Consequence

CYB5R3
ENST00000352397.10 splice_donor_region, intron

Scores

Splicing: ADA: 0.00005001

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.24

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 22-42649289-G-A is Benign according to our data. Variant chr22-42649289-G-A is described in ClinVar as [Benign]. Clinvar id is 994069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-42649289-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYB5R3	NM_000398.7 linkuse as main transcript	c.21+6C>T		splice_donor_region_variant, intron_variant		ENST00000352397.10	NP_000389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000352397.10 linkuse as main transcript	c.21+6C>T		splice_donor_region_variant, intron_variant		1	NM_000398.7	ENSP00000338461	P3	P00387-1

Frequencies

GnomAD3 genomes

AF:

0.0158

AC:

2352

AN:

148550

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0543

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00555

Gnomad ASJ

AF:

0.000294

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.000210

Gnomad OTH

AF:

0.00978

GnomAD3 exomes

AF:

0.00154

AC:

AN:

3254

Hom.:

AF XY:

0.00145

AC XY:

AN XY:

2072

show subpopulations

Gnomad AFR exome

AF:

0.0690

Gnomad AMR exome

AF:

0.00238

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00126

AC:

1079

AN:

854988

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

480

AN XY:

405280

show subpopulations

Gnomad4 AFR exome

AF:

0.0559

Gnomad4 AMR exome

AF:

0.00388

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000179

Gnomad4 SAS exome

AF:

0.000161

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000870

Gnomad4 OTH exome

AF:

0.00296

GnomAD4 genome

AF:

0.0158

AC:

2356

AN:

148658

Hom.:

Cov.:

AF XY:

0.0153

AC XY:

1106

AN XY:

72486

show subpopulations

Gnomad4 AFR

AF:

0.0543

Gnomad4 AMR

AF:

0.00554

Gnomad4 ASJ

AF:

0.000294

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000210

Gnomad4 OTH

AF:

0.00967

Alfa

AF:

0.0102

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

CYB5R3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.97

RBP_binding_hub_radar

0.67

RBP_regulation_power_radar

3.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000050

dbscSNV1_RF

Benign

0.0060

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over