NM_022482.5:c.1054dupA

Variant names:

• chr20-23365436-C-CA
• rs1555786729
• NM_022482.5:c.1054dupA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_022482.5(GZF1):​c.1054dupA​(p.Thr352AsnfsTer50) variant causes a frameshift change. 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. T352T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GZF1 NM_022482.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.47
• Publications: 1 publications found

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]

GZF1 Gene-Disease associations (from GenCC):

• joint laxity, short stature, and myopia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Larsen syndrome

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-23365436-C-CA is Pathogenic according to our data. Variant chr20-23365436-C-CA is described in ClinVar as Pathogenic. ClinVar VariationId is 438349.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022482.5. 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
	GZF1	NM_022482.5	MANE Select	c.1054dupA	p.Thr352AsnfsTer50	frameshift	Exon 2 of 6	NP_071927.1	Q9H116-1
	GZF1	NM_001317012.2		c.1054dupA	p.Thr352AsnfsTer50	frameshift	Exon 3 of 7	NP_001303941.1	Q9H116-1
	GZF1	NM_001317019.1		c.1054dupA	p.Thr352AsnfsTer50	frameshift	Exon 1 of 5	NP_001303948.1	Q9H116

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GZF1	ENST00000338121.10	TSL:1 MANE Select	c.1054dupA	p.Thr352AsnfsTer50	frameshift	Exon 2 of 6	ENSP00000338290.5	Q9H116-1
	GZF1	ENST00000377051.2	TSL:1	c.1054dupA	p.Thr352AsnfsTer50	frameshift	Exon 1 of 5	ENSP00000366250.2	Q9H116-1
	GZF1	ENST00000907448.1		c.1054dupA	p.Thr352AsnfsTer50	frameshift	Exon 2 of 7	ENSP00000577507.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Joint laxity, short stature, and myopia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5
Mutation Taster		=4/196	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555786729; hg19: chr20-23346073;