22-42619789-C-T

Position:

chr22-42619789-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000398.7(CYB5R3):c.890G>A(p.Arg297His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,587,798 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 13 hom. )

Consequence

CYB5R3
NM_000398.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 1.19

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 -11 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=0.007664025).

BP6

Variant 22-42619789-C-T is Benign according to our data. Variant chr22-42619789-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 694657.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}. Variant chr22-42619789-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00158 (241/152262) while in subpopulation SAS AF= 0.00538 (26/4832). AF 95% confidence interval is 0.00377. There are 0 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYB5R3	NM_000398.7 link	c.890G>A	p.Arg297His	missense_variant	9/9	ENST00000352397.10	NP_000389.1	P00387-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000352397.10 link	c.890G>A	p.Arg297His	missense_variant	9/9	1	NM_000398.7	ENSP00000338461.6		P00387-1
ENSG00000289517	ENST00000617178.5 link	n.425G>A		non_coding_transcript_exon_variant	4/14	1		ENSP00000482500.2		A0A087WZB1

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

240

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00517

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00247

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00209

AC:

434

AN:

208038

Hom.:

AF XY:

0.00237

AC XY:

266

AN XY:

112172

show subpopulations

Gnomad AFR exome

AF:

0.000463

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.000657

Gnomad EAS exome

AF:

0.0000631

Gnomad SAS exome

AF:

0.00642

Gnomad FIN exome

AF:

0.000135

Gnomad NFE exome

AF:

0.00201

Gnomad OTH exome

AF:

0.00248

GnomAD4 exome

AF:

0.00230

AC:

3301

AN:

1435536

Hom.:

Cov.:

AF XY:

0.00247

AC XY:

1761

AN XY:

711722

show subpopulations

Gnomad4 AFR exome

AF:

0.000541

Gnomad4 AMR exome

AF:

0.00144

Gnomad4 ASJ exome

AF:

0.000666

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00680

Gnomad4 FIN exome

AF:

0.0000628

Gnomad4 NFE exome

AF:

0.00219

Gnomad4 OTH exome

AF:

0.00242

GnomAD4 genome

AF:

0.00158

AC:

241

AN:

152262

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000458

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00538

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00247

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00258

Hom.:

Bravo

AF:

0.00150

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00169

AC:

204

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	CYB5R3: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 13, 2024	BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

Neurodevelopmental delay

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Sep 22, 2018

- -

CYB5R3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 14, 2023

This variant is classified as likely 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

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;T;.;.;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.096

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.84

T;T;.;.;T

MetaRNN

Benign

0.0077

T;T;T;T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

1.3

.;L;.;.;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.9

N;N;N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.077

T;T;T;T;T

Sift4G

Benign

0.087

T;T;T;T;T

Polyphen

0.084

.;B;.;.;.

Vest4

0.11

MVP

0.96

MPC

0.043

ClinPred

0.029

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.091

gMVP

0.60

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