Genetic Variant BLVRB:p.Asp60Tyr (chr19-40458447-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000713.3(BLVRB):c.178G>T(p.Asp60Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,445,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. D60N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BLVRB
NM_000713.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.36

Publications

0 publications found

Variant links:

Genes affected

BLVRB (HGNC:1063): (biliverdin reductase B) Enables biliverdin reductase (NAD(P)+) activity and riboflavin reductase (NADPH) activity. Involved in heme catabolic process. Located in cytosol; nucleoplasm; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

BLVRB links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.825

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000713.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLVRB	NM_000713.3	MANE Select	c.178G>T	p.Asp60Tyr	missense	Exon 2 of 5	NP_000704.1	P30043

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BLVRB	ENST00000263368.9	TSL:1 MANE Select	c.178G>T	p.Asp60Tyr	missense	Exon 2 of 5	ENSP00000263368.3	P30043
BLVRB	ENST00000643519.1		c.178G>T	p.Asp60Tyr	missense	Exon 2 of 4	ENSP00000494515.1	A0A2R8YEP4
BLVRB	ENST00000926837.1		c.178G>T	p.Asp60Tyr	missense	Exon 2 of 5	ENSP00000596896.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445660

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717650

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33230

American (AMR)

AF:

0.00

AC:

AN:

42448

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25716

East Asian (EAS)

AF:

0.00

AC:

AN:

38966

South Asian (SAS)

AF:

0.00

AC:

AN:

83400

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1104936

Other (OTH)

AF:

0.00

AC:

AN:

59728

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.32

MutationAssessor

Pathogenic

3.4

PhyloP100

5.4

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-6.7

REVEL

Uncertain

0.50

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.69

MutPred

0.63

Loss of disorder (P = 0.0806)

MVP

0.47

MPC

0.85

ClinPred

1.0

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.92

gMVP

0.84

Mutation Taster

=12/88

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over