1-169380608-A-G

Variant names:

• chr1-169380608-A-G
• NM_001320973.2:c.796A>G

Variant summary

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

The NM_001320973.2(BLZF1):​c.796A>G​(p.Lys266Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,272 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BLZF1 NM_001320973.2 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.42

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 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
BLZF1	NM_001320973.2	c.796A>G	p.Lys266Glu	missense_variant, splice_region_variant	Exon 5 of 7	ENST00000367808.8	NP_001307902.1
BLZF1	NM_003666.4	c.796A>G	p.Lys266Glu	missense_variant, splice_region_variant	Exon 5 of 8		NP_003657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLZF1	ENST00000367808.8	c.796A>G	p.Lys266Glu	missense_variant, splice_region_variant	Exon 5 of 7	1	NM_001320973.2	ENSP00000356782.3
BLZF1	ENST00000329281.6	c.796A>G	p.Lys266Glu	missense_variant, splice_region_variant	Exon 5 of 8	1		ENSP00000327541.2
BLZF1	ENST00000426663.1	c.*46A>G		downstream_gene_variant		3		ENSP00000404408.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460272 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726442

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.796A>G (p.K266E) alteration is located in exon 5 (coding exon 4) of the BLZF1 gene. This alteration results from a A to G substitution at nucleotide position 796, causing the lysine (K) at amino acid position 266 to be replaced by a glutamic acid (E). 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	0.14
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;.
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.032	D;D
Polyphen		0.77	P;P
Vest4		0.57
MutPred		0.29		Loss of ubiquitination at K266 (P = 0.0218);Loss of ubiquitination at K266 (P = 0.0218);
MVP		0.36
MPC		0.23
ClinPred		0.86	D
GERP RS		5.5
Varity_R		0.32
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-169349846;