Genetic Variant CBR1:p.Phe95Leu (chr21-36070400-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001757.4(CBR1):c.285C>A(p.Phe95Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CBR1
NM_001757.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.791

Variant links:

Genes affected

CBR1 (HGNC:1548): (carbonyl reductase 1) The protein encoded by this gene belongs to the short-chain dehydrogenases/reductases (SDR) family, which function as NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds, such as quinones, prostaglandins, and various xenobiotics. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2013]

CBR1 links:

SETD4 (HGNC:1258): (SET domain containing 4) Enables histone methyltransferase activity (H4-K20 specific). Involved in histone H4-K20 trimethylation. Located in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SETD4 links:

CBR1-AS1 (HGNC:55777): (CBR1 antisense RNA 1)

CBR1-AS1 links:

ENSG00000289001 (HGNC:):

ENSG00000289001 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBR1	NM_001757.4 link	c.285C>A	p.Phe95Leu	missense_variant	Exon 1 of 3	ENST00000290349.11	NP_001748.1	P16152-1A0A384NL53
CBR1	NM_001286789.2 link	c.285C>A	p.Phe95Leu	missense_variant	Exon 1 of 3		NP_001273718.1	P16152-2
CBR1-AS1	NR_040084.1 link	n.463G>T		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBR1	ENST00000290349.11 link	c.285C>A	p.Phe95Leu	missense_variant	Exon 1 of 3	1	NM_001757.4	ENSP00000290349.6		P16152-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000426

AC:

AN:

234524

Hom.:

AF XY:

0.00000783

AC XY:

AN XY:

127728

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000963

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1450250

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720468

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.285C>A (p.F95L) alteration is located in exon 1 (coding exon 1) of the CBR1 gene. This alteration results from a C to A substitution at nucleotide position 285, causing the phenylalanine (F) at amino acid position 95 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Uncertain

0.57

.;D;.;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.58

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

T;T;T;T

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.45

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.025

N;N;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.3

D;D;D;D

REVEL

Benign

0.24

Sift

Benign

0.13

T;T;D;D

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.0010, 0.0030

.;B;B;.

Vest4

0.88

MutPred

0.47

Loss of catalytic residue at F95 (P = 0.0025);Loss of catalytic residue at F95 (P = 0.0025);Loss of catalytic residue at F95 (P = 0.0025);Loss of catalytic residue at F95 (P = 0.0025);

MVP

0.11

MPC

0.34

ClinPred

0.48

GERP RS

2.9

Varity_R

0.64

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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