Genetic Variant NM_016243.3:c.131A>G (chr1-202966783-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_016243.3(CYB5R1):c.131A>G(p.Asn44Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0626 in 1,613,964 control chromosomes in the GnomAD database, including 8,611 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.097 ( 1324 hom., cov: 31)

Exomes 𝑓: 0.059 ( 7287 hom. )

Consequence

CYB5R1
NM_016243.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.890

Publications

21 publications found

Variant links:

Genes affected

CYB5R1 (HGNC:13397): (cytochrome b5 reductase 1) Predicted to enable FAD binding activity. Predicted to be involved in bicarbonate transport. Located in extracellular exosome; membrane; and mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

CYB5R1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020075738).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5R1	NM_016243.3 link	c.131A>G	p.Asn44Ser	missense_variant	Exon 2 of 9	ENST00000367249.9	NP_057327.2	Q9UHQ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5R1	ENST00000367249.9 link	c.131A>G	p.Asn44Ser	missense_variant	Exon 2 of 9	1	NM_016243.3	ENSP00000356218.4		Q9UHQ9

Frequencies

GnomAD3 genomes

AF:

0.0964

AC:

14660

AN:

152060

Hom.:

1308

Cov.:

show subpopulations

Gnomad AFR

AF:

0.148

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.154

Gnomad ASJ

AF:

0.0205

Gnomad EAS

AF:

0.431

Gnomad SAS

AF:

0.163

Gnomad FIN

AF:

0.0785

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0302

Gnomad OTH

AF:

0.0859

GnomAD2 exomes

AF:

0.115

AC:

28863

AN:

251196

AF XY:

0.107

show subpopulations

Gnomad AFR exome

AF:

0.148

Gnomad AMR exome

AF:

0.233

Gnomad ASJ exome

AF:

0.0171

Gnomad EAS exome

AF:

0.435

Gnomad FIN exome

AF:

0.0823

Gnomad NFE exome

AF:

0.0297

Gnomad OTH exome

AF:

0.0847

GnomAD4 exome

AF:

0.0591

AC:

86368

AN:

1461786

Hom.:

7287

Cov.:

AF XY:

0.0604

AC XY:

43946

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.146

AC:

4875

AN:

33478

American (AMR)

AF:

0.226

AC:

10085

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

453

AN:

26120

East Asian (EAS)

AF:

0.431

AC:

17107

AN:

39698

South Asian (SAS)

AF:

0.147

AC:

12668

AN:

86256

European-Finnish (FIN)

AF:

0.0782

AC:

4174

AN:

53410

Middle Eastern (MID)

AF:

0.0373

AC:

215

AN:

5768

European-Non Finnish (NFE)

AF:

0.0292

AC:

32501

AN:

1111946

Other (OTH)

AF:

0.0710

AC:

4290

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

4333

8666

12998

17331

21664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1712

3424

5136

6848

8560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0967

AC:

14712

AN:

152178

Hom.:

1324

Cov.:

AF XY:

0.103

AC XY:

7665

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.148

AC:

6157

AN:

41510

American (AMR)

AF:

0.155

AC:

2366

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0205

AC:

AN:

3470

East Asian (EAS)

AF:

0.432

AC:

2226

AN:

5154

South Asian (SAS)

AF:

0.163

AC:

789

AN:

4828

European-Finnish (FIN)

AF:

0.0785

AC:

833

AN:

10608

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0302

AC:

2055

AN:

68006

Other (OTH)

AF:

0.0926

AC:

195

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

639

1278

1916

2555

3194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

328

492

656

820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0576

Hom.:

2994

Bravo

AF:

0.105

TwinsUK

AF:

0.0267

AC:

ALSPAC

AF:

0.0262

AC:

101

ESP6500AA

AF:

0.147

AC:

648

ESP6500EA

AF:

0.0276

AC:

237

ExAC

AF:

0.109

AC:

13198

Asia WGS

AF:

0.283

AC:

981

AN:

3478

EpiCase

AF:

0.0276

EpiControl

AF:

0.0244

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.019

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

0.89

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

REVEL

Benign

0.19

Sift

Benign

0.57

Sift4G

Benign

0.62

Polyphen

0.0010

Vest4

0.14

MPC

0.080

ClinPred

0.00069

GERP RS

3.4

PromoterAI

-0.029

Neutral

(source)

Varity_R

0.041

gMVP

0.52

Mutation Taster

=92/8

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over