rs8133052

Positions:

• chr21-36135203-G-A
• chr21-36135203-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001236.4(CBR3):​c.11G>A​(p.Cys4Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 1,496,066 control chromosomes in the GnomAD database, including 148,088 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.40 (12552 hom., cov: 34)
  • Exomes 𝑓: 0.45 (135536 hom.)
• Consequence: CBR3 NM_001236.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.163

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

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9779801E-4).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBR3	NM_001236.4	c.11G>A	p.Cys4Tyr	missense_variant	1/3	ENST00000290354.6	NP_001227.1
CBR3-AS1	NR_038893.1	n.193-2129C>T		intron_variant, non_coding_transcript_variant
CBR3	XM_011529772.3	c.11G>A	p.Cys4Tyr	missense_variant	1/3		XP_011528074.1
CBR3-AS1	NR_038892.1	n.193-1442C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBR3	ENST00000290354.6	c.11G>A	p.Cys4Tyr	missense_variant	1/3	1	NM_001236.4	ENSP00000290354	P1
CBR3-AS1	ENST00000624080.1	n.149-1730C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60356 AN: 152018 Hom.: 12544 Cov.: 34

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.434

GnomAD3 exomes AF: 0.439 AC: 49376 AN: 112494 Hom.: 10957 AF XY: 0.436 AC XY: 25741 AN XY: 59056

Gnomad AFR exome AF: 0.296

Gnomad AMR exome AF: 0.492

Gnomad ASJ exome AF: 0.400

Gnomad EAS exome AF: 0.452

Gnomad SAS exome AF: 0.321

Gnomad FIN exome AF: 0.431

Gnomad NFE exome AF: 0.473

Gnomad OTH exome AF: 0.446

GnomAD4 exome AF: 0.446 AC: 599969 AN: 1343934 Hom.: 135536 Cov.: 48 AF XY: 0.444 AC XY: 291464 AN XY: 657002

Gnomad4 AFR exome AF: 0.280

Gnomad4 AMR exome AF: 0.486

Gnomad4 ASJ exome AF: 0.383

Gnomad4 EAS exome AF: 0.454

Gnomad4 SAS exome AF: 0.318

Gnomad4 FIN exome AF: 0.422

Gnomad4 NFE exome AF: 0.462

Gnomad4 OTH exome AF: 0.428

GnomAD4 genome AF: 0.397 AC: 60403 AN: 152132 Hom.: 12552 Cov.: 34 AF XY: 0.396 AC XY: 29413 AN XY: 74368

Gnomad4 AFR AF: 0.282

Gnomad4 AMR AF: 0.475

Gnomad4 ASJ AF: 0.381

Gnomad4 EAS AF: 0.438

Gnomad4 SAS AF: 0.301

Gnomad4 FIN AF: 0.407

Gnomad4 NFE AF: 0.453

Gnomad4 OTH AF: 0.434

Alfa AF: 0.445 Hom.: 20695

Bravo AF: 0.401

TwinsUK AF: 0.471 AC: 1746

ALSPAC AF: 0.466 AC: 1797

ESP6500AA AF: 0.270 AC: 1102

ESP6500EA AF: 0.425 AC: 3407

ExAC AF: 0.328 AC: 34990

Asia WGS AF: 0.355 AC: 1232 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.00020	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.040	N
MutationTaster	Benign	0.020	P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.090
Sift	Benign	0.37	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.045
MPC		0.33
ClinPred		0.011	T
GERP RS		2.5
Varity_R		0.12
gMVP		0.41

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

Other links and lift over

dbSNP: rs8133052; hg19: chr21-37507501; COSMIC: COSV51740640; COSMIC: COSV51740640;