20-23364392-C-T

Variant names:

• chr20-23364392-C-T
• rs576902241
• NM_022482.5:c.9C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Strong BP6_Moderate BP7 BS1

The NM_022482.5(GZF1):​c.9C>T​(p.Ser3Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000153 in 1,563,608 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (1 hom.)
• Consequence: GZF1 NM_022482.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.514
• 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: Benign. The variant received -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 20-23364392-C-T is Benign according to our data. Variant chr20-23364392-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2419655.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.514 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000131 (2/152308) while in subpopulation SAS AF = 0.000414 (2/4828). AF 95% confidence interval is 0.0000729. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.9C>T	p.Ser3Ser	synonymous	Exon 2 of 6	NP_071927.1	Q9H116-1
	GZF1	NM_001317012.2		c.9C>T	p.Ser3Ser	synonymous	Exon 3 of 7	NP_001303941.1	Q9H116-1
	GZF1	NM_001317019.1		c.9C>T	p.Ser3Ser	synonymous	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.9C>T	p.Ser3Ser	synonymous	Exon 2 of 6	ENSP00000338290.5	Q9H116-1
	GZF1	ENST00000377051.2	TSL:1	c.9C>T	p.Ser3Ser	synonymous	Exon 1 of 5	ENSP00000366250.2	Q9H116-1
	GZF1	ENST00000907448.1		c.9C>T	p.Ser3Ser	synonymous	Exon 2 of 7	ENSP00000577507.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000404 AC: 9 AN: 222922 AF XY: 0.0000416

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000960

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000156 AC: 22 AN: 1411300 Hom.: 1 Cov.: 30 AF XY: 0.0000172 AC XY: 12 AN XY: 696238

African (AFR) AF: 0.0000317 AC: 1 AN: 31564

American (AMR) AF: 0.0000817 AC: 3 AN: 36736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23588

East Asian (EAS) AF: 0.00 AC: 0 AN: 39014

South Asian (SAS) AF: 0.0000872 AC: 7 AN: 80302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5532

European-Non Finnish (NFE) AF: 0.0000101 AC: 11 AN: 1084410

Other (OTH) AF: 0.00 AC: 0 AN: 58024

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.71
PhyloP100		0.51
PromoterAI		0.0074	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs576902241; hg19: chr20-23345029;