Genetic Variant NM_001236.4:c.730G>A (chr21-36146408-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001236.4(CBR3):c.730G>A(p.Val244Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 1,613,776 control chromosomes in the GnomAD database, including 112,002 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.39 ( 11709 hom., cov: 32)

Exomes 𝑓: 0.37 ( 100293 hom. )

Consequence

CBR3
NM_001236.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.87

Publications

130 publications found

Variant links:

Genes affected

CBR3 (HGNC:1549): (carbonyl reductase 3) Carbonyl reductase 3 catalyzes the reduction of a large number of biologically and pharmacologically active carbonyl compounds to their corresponding alcohols. The enzyme is classified as a monomeric NADPH-dependent oxidoreductase. CBR3 contains three exons spanning 11.2 kilobases and is closely linked to another carbonyl reductase gene - CBR1. [provided by RefSeq, Jul 2008]

CBR3 links:

CBR3-AS1 (HGNC:43664): (CBR3 antisense RNA 1)

CBR3-AS1 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=0.001534909).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.482 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CBR3	NM_001236.4 link	c.730G>A	p.Val244Met	missense_variant	Exon 3 of 3	ENST00000290354.6	NP_001227.1
CBR3-AS1	NR_038892.1 link	n.93-53C>T		intron_variant	Intron 1 of 3
CBR3-AS1	NR_038893.1 link	n.93-53C>T		intron_variant	Intron 1 of 2
CBR3-AS1	NR_038894.1 link	n.93-53C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBR3	ENST00000290354.6 link	c.730G>A	p.Val244Met	missense_variant	Exon 3 of 3	1	NM_001236.4	ENSP00000290354.5		O75828

Frequencies

GnomAD3 genomes

AF:

0.387

AC:

58757

AN:

151888

Hom.:

11707

Cov.:

show subpopulations

Gnomad AFR

AF:

0.468

Gnomad AMI

AF:

0.390

Gnomad AMR

AF:

0.296

Gnomad ASJ

AF:

0.401

Gnomad EAS

AF:

0.404

Gnomad SAS

AF:

0.499

Gnomad FIN

AF:

0.329

Gnomad MID

AF:

0.427

Gnomad NFE

AF:

0.357

Gnomad OTH

AF:

0.365

GnomAD2 exomes

AF:

0.367

AC:

92349

AN:

251384

AF XY:

0.374

show subpopulations

Gnomad AFR exome

AF:

0.474

Gnomad AMR exome

AF:

0.272

Gnomad ASJ exome

AF:

0.403

Gnomad EAS exome

AF:

0.417

Gnomad FIN exome

AF:

0.320

Gnomad NFE exome

AF:

0.348

Gnomad OTH exome

AF:

0.356

GnomAD4 exome

AF:

0.367

AC:

535955

AN:

1461772

Hom.:

100293

Cov.:

AF XY:

0.370

AC XY:

269176

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.481

AC:

16096

AN:

33476

American (AMR)

AF:

0.275

AC:

12319

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.405

AC:

10583

AN:

26130

East Asian (EAS)

AF:

0.396

AC:

15704

AN:

39700

South Asian (SAS)

AF:

0.478

AC:

41240

AN:

86254

European-Finnish (FIN)

AF:

0.311

AC:

16610

AN:

53416

Middle Eastern (MID)

AF:

0.454

AC:

2617

AN:

5768

European-Non Finnish (NFE)

AF:

0.358

AC:

397902

AN:

1111914

Other (OTH)

AF:

0.379

AC:

22884

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

20083

40167

60250

80334

100417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12872

25744

38616

51488

64360

<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:

0.387

AC:

58788

AN:

152004

Hom.:

11709

Cov.:

AF XY:

0.384

AC XY:

28566

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.468

AC:

19406

AN:

41438

American (AMR)

AF:

0.296

AC:

4512

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.401

AC:

1393

AN:

3470

East Asian (EAS)

AF:

0.404

AC:

2089

AN:

5170

South Asian (SAS)

AF:

0.499

AC:

2406

AN:

4822

European-Finnish (FIN)

AF:

0.329

AC:

3478

AN:

10576

Middle Eastern (MID)

AF:

0.425

AC:

125

AN:

294

European-Non Finnish (NFE)

AF:

0.357

AC:

24259

AN:

67956

Other (OTH)

AF:

0.362

AC:

765

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1796

3591

5387

7182

8978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

570

1140

1710

2280

2850

<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:

0.368

Hom.:

41301

Bravo

AF:

0.387

TwinsUK

AF:

0.354

AC:

1312

ALSPAC

AF:

0.360

AC:

1388

ESP6500AA

AF:

0.475

AC:

2092

ESP6500EA

AF:

0.360

AC:

3094

ExAC

AF:

0.374

AC:

45404

Asia WGS

AF:

0.436

AC:

1517

AN:

3478

EpiCase

AF:

0.356

EpiControl

AF:

0.354

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.021

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.8

PhyloP100

2.9

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.63

REVEL

Benign

0.084

Sift

Benign

0.069

Sift4G

Benign

0.077

Polyphen

0.62

Vest4

0.038

MPC

0.35

ClinPred

0.010

GERP RS

0.55

Varity_R

0.094

gMVP

0.33

Mutation Taster

=65/35

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