dbSNP rs75478217: CYB5R3:p.Ala158Pro (chr22-42627680-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_000398.7(CYB5R3):c.472G>C(p.Ala158Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,932 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A158T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CYB5R3
NM_000398.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.86

Publications

3 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:

ENSG00000289517 (HGNC:):

ENSG00000289517 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a chain NADH-cytochrome b5 reductase 3 (size 299) in uniprot entity NB5R3_HUMAN there are 20 pathogenic changes around while only 7 benign (74%) in NM_000398.7

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5R3	NM_000398.7 link	c.472G>C	p.Ala158Pro	missense_variant	Exon 6 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.472G>C	p.Ala158Pro	missense_variant	Exon 6 of 9	1	NM_000398.7	ENSP00000338461.6		P00387-1
ENSG00000289517	ENST00000617178.5 link	n.7G>C		non_coding_transcript_exon_variant	Exon 1 of 14	1		ENSP00000482500.2		A0A087WZB1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460932

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726840

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111150

Other (OTH)

AF:

0.00

AC:

AN:

60368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

.;T;.;.;.;T

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D;.;.;T;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.60

D;D;D;D;D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

0.42

.;N;.;.;.;.

PhyloP100

4.9

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.2

D;D;D;D;D;D

REVEL

Pathogenic

0.66

Sift

Benign

0.16

T;T;T;T;T;T

Sift4G

Benign

0.16

T;T;T;T;T;.

Polyphen

0.097

.;B;.;.;.;.

Vest4

0.65

MutPred

0.42

.;Gain of disorder (P = 0.0294);.;.;.;.;

MVP

0.96

MPC

0.28

ClinPred

0.98

GERP RS

3.7

Varity_R

0.82

gMVP

0.80

Mutation Taster

=43/57

disease causing

(source)

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

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rs75478217

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over