dbSNP rs1366655332: BLZF1:p.Gln186Lys (chr1-169378417-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001320973.2(BLZF1):c.556C>A(p.Gln186Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,948 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q186E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BLZF1
NM_001320973.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.33

Publications

0 publications found

Variant links:

Genes affected

BLZF1 (HGNC:1065): (basic leucine zipper nuclear factor 1) Enables ubiquitin protein ligase binding activity. Acts upstream of or within Golgi organization and Golgi to plasma membrane protein transport. Located in Golgi apparatus and nucleoplasm. Biomarker of hepatocellular carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

BLZF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320973.2. 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
	BLZF1	NM_001320973.2	MANE Select	c.556C>A	p.Gln186Lys	missense	Exon 4 of 7	NP_001307902.1	Q9H2G9-1
	BLZF1	NM_003666.4		c.556C>A	p.Gln186Lys	missense	Exon 4 of 8	NP_003657.1	Q9H2G9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BLZF1	ENST00000367808.8	TSL:1 MANE Select	c.556C>A	p.Gln186Lys	missense	Exon 4 of 7	ENSP00000356782.3	Q9H2G9-1
BLZF1	ENST00000329281.6	TSL:1	c.556C>A	p.Gln186Lys	missense	Exon 4 of 8	ENSP00000327541.2	Q9H2G9-1
BLZF1	ENST00000899417.1		c.556C>A	p.Gln186Lys	missense	Exon 4 of 7	ENSP00000569476.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460948

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726796

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:

33438

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111306

Other (OTH)

AF:

0.00

AC:

AN:

60352

⚠️ 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: 0.325

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

Benign

0.19

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.027

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.60

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

7.3

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.27

Sift

Benign

0.23

Sift4G

Benign

0.18

Polyphen

0.78

Vest4

0.64

MutPred

0.64

Gain of ubiquitination at Q186 (P = 0.023)

MVP

0.53

MPC

0.45

ClinPred

0.95

GERP RS

6.2

Varity_R

0.30

gMVP

0.40

Mutation Taster

=37/63

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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