1-169376966-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001320973.2(BLZF1):c.455G>T(p.Arg152Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BLZF1 NM_001320973.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41272715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLZF1	NM_001320973.2	c.455G>T	p.Arg152Leu	missense_variant	3/7	ENST00000367808.8
BLZF1	NM_003666.4	c.455G>T	p.Arg152Leu	missense_variant	3/8
BLZF1	NM_001320972.2	c.455G>T	p.Arg152Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLZF1	ENST00000367808.8	c.455G>T	p.Arg152Leu	missense_variant	3/7	1	NM_001320973.2	P1
BLZF1	ENST00000329281.6	c.455G>T	p.Arg152Leu	missense_variant	3/8	1		P1
BLZF1	ENST00000367807.7	c.455G>T	p.Arg152Leu	missense_variant	3/3	1
BLZF1	ENST00000426663.1	c.455G>T	p.Arg152Leu	missense_variant	3/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248148 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460398 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726538

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2024

The c.455G>T (p.R152L) alteration is located in exon 3 (coding exon 2) of the BLZF1 gene. This alteration results from a G to T substitution at nucleotide position 455, causing the arginine (R) at amino acid position 152 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	Benign	0.24
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;.;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.5	M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.2	D;D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.024	D;T;T;T
Polyphen		1.0	D;P;P;.
Vest4		0.71
MutPred		0.37		Loss of MoRF binding (P = 0.0047);Loss of MoRF binding (P = 0.0047);Loss of MoRF binding (P = 0.0047);Loss of MoRF binding (P = 0.0047);
MVP		0.54
MPC		0.29
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.19
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs369684533; hg19: chr1-169346204;