20-23364430-AC-A

Variant names:

• chr20-23364430-AC-A
• NM_022482.5:c.49delC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_022482.5(GZF1):​c.49delC​(p.Leu17TyrfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L17L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GZF1 NM_022482.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.02

Genes affected

GZF1 (HGNC:15808): (GDNF inducible zinc finger protein 1) Enables DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in negative regulation of transcription by RNA polymerase II. Located in nucleolus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-23364430-AC-A is Pathogenic according to our data. Variant chr20-23364430-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 2841879.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GZF1	NM_022482.5	c.49delC	p.Leu17TyrfsTer17	frameshift_variant	Exon 2 of 6	ENST00000338121.10	NP_071927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GZF1	ENST00000338121.10	c.49delC	p.Leu17TyrfsTer17	frameshift_variant	Exon 2 of 6	1	NM_022482.5	ENSP00000338290.5
GZF1	ENST00000377051.2	c.49delC	p.Leu17TyrfsTer17	frameshift_variant	Exon 1 of 5	1		ENSP00000366250.2
GZF1	ENST00000424216.1	c.49delC	p.Leu17TyrfsTer17	frameshift_variant	Exon 3 of 3	5		ENSP00000410009.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Mar 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with GZF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu17Tyrfs*17) in the GZF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GZF1 are known to be pathogenic (PMID: 28475863). -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-23345067;