22-42619781-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000398.7(CYB5R3):c.898G>A(p.Val300Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,582,544 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0075 ( 15 hom., cov: 33)

Exomes 𝑓: 0.00084 ( 13 hom. )

Consequence

CYB5R3
NM_000398.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.48

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:

ENSG00000289517 (HGNC:):

ENSG00000289517 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain NADH-cytochrome b5 reductase 3 (size 299) in uniprot entity NB5R3_HUMAN there are 51 pathogenic changes around while only 3 benign (94%) in NM_000398.7

BP4

Computational evidence support a benign effect (MetaRNN=0.00615865).

BP6

Variant 22-42619781-C-T is Benign according to our data. Variant chr22-42619781-C-T is described in ClinVar as [Benign]. Clinvar id is 778955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00749 (1140/152248) while in subpopulation AFR AF= 0.0256 (1063/41546). AF 95% confidence interval is 0.0243. There are 15 homozygotes in gnomad4. There are 541 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5R3	NM_000398.7 link	c.898G>A	p.Val300Ile	missense_variant	Exon 9 of 9	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.898G>A	p.Val300Ile	missense_variant	Exon 9 of 9	1	NM_000398.7	ENSP00000338461.6		P00387-1
ENSG00000289517	ENST00000617178.5 link	n.433G>A		non_coding_transcript_exon_variant	Exon 4 of 14	1		ENSP00000482500.2		A0A087WZB1

Frequencies

GnomAD3 genomes

AF:

0.00747

AC:

1136

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0256

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00202

AC:

407

AN:

201626

Hom.:

AF XY:

0.00154

AC XY:

167

AN XY:

108648

show subpopulations

Gnomad AFR exome

AF:

0.0273

Gnomad AMR exome

AF:

0.00160

Gnomad ASJ exome

AF:

0.000111

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000382

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000165

Gnomad OTH exome

AF:

0.000974

GnomAD4 exome

AF:

0.000836

AC:

1196

AN:

1430296

Hom.:

Cov.:

AF XY:

0.000728

AC XY:

516

AN XY:

708648

show subpopulations

Gnomad4 AFR exome

AF:

0.0270

Gnomad4 AMR exome

AF:

0.00154

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000259

Gnomad4 SAS exome

AF:

0.0000607

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000928

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.00749

AC:

1140

AN:

152248

Hom.:

Cov.:

AF XY:

0.00727

AC XY:

541

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0256

Gnomad4 AMR

AF:

0.00320

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.000960

Hom.:

Bravo

AF:

0.00853

ESP6500AA

AF:

0.0257

AC:

113

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00221

AC:

266

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

0.059

DANN

Benign

0.93

DEOGEN2

Benign

0.10

.;T;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.28

T;T;.;.;T

MetaRNN

Benign

0.0062

T;T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.40

.;N;.;.;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.67

N;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.28

T;T;T;T;T

Sift4G

Benign

0.28

T;T;T;T;T

Polyphen

0.0

.;B;.;.;.

Vest4

0.012

MVP

0.49

MPC

0.033

ClinPred

0.00091

GERP RS

-6.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.030

gMVP

0.21

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

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