22-42628265-G-C

Position:

chr22-42628265-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000398.7(CYB5R3):c.350C>G(p.Thr117Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,613,922 control chromosomes in the GnomAD database, including 3,151 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.080 ( 1670 hom., cov: 32)

Exomes 𝑓: 0.0082 ( 1481 hom. )

Consequence

CYB5R3
NM_000398.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.08

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 -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=0.0022090673).

BP6

Variant 22-42628265-G-C is Benign according to our data. Variant chr22-42628265-G-C is described in ClinVar as [Benign]. Clinvar id is 244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 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.350C>G	p.Thr117Ser	missense_variant	5/9	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.350C>G	p.Thr117Ser	missense_variant	5/9	1	NM_000398.7	ENSP00000338461	P3	P00387-1

Frequencies

GnomAD3 genomes

AF:

0.0802

AC:

12187

AN:

152042

Hom.:

1671

Cov.:

show subpopulations

Gnomad AFR

AF:

0.281

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0263

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.0498

GnomAD3 exomes

AF:

0.0207

AC:

5217

AN:

251468

Hom.:

655

AF XY:

0.0151

AC XY:

2053

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.286

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.00317

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000633

Gnomad OTH exome

AF:

0.00782

GnomAD4 exome

AF:

0.00815

AC:

11920

AN:

1461762

Hom.:

1481

Cov.:

AF XY:

0.00709

AC XY:

5156

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.283

Gnomad4 AMR exome

AF:

0.0141

Gnomad4 ASJ exome

AF:

0.00333

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000684

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000505

Gnomad4 OTH exome

AF:

0.0172

GnomAD4 genome

AF:

0.0801

AC:

12190

AN:

152160

Hom.:

1670

Cov.:

AF XY:

0.0771

AC XY:

5738

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.280

Gnomad4 AMR

AF:

0.0263

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000838

Gnomad4 OTH

AF:

0.0492

Alfa

AF:

0.00431

Hom.:

Bravo

AF:

0.0907

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.275

AC:

1211

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.0258

AC:

3130

EpiCase

AF:

0.000709

EpiControl

AF:

0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 21085059) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

NADH-CYTOCHROME b5 REDUCTASE POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

May 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.35

.;T;.;.;.;T

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.74

T;T;.;.;T;T

MetaRNN

Benign

0.0022

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.68

.;N;.;.;.;.

MutationTaster

Benign

0.73

P;P;P;P;P;P

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.5

D;D;N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.10

T;T;T;T;T;T

Sift4G

Benign

0.18

T;T;T;T;T;.

Polyphen

0.0

.;B;.;.;.;.

Vest4

0.070

MutPred

0.14

.;Gain of disorder (P = 0.0511);.;.;.;.;

MPC

0.036

ClinPred

0.016

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.28

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