20-23364496-A-C

Variant names:

• chr20-23364496-A-C
• rs1162238866
• NM_022482.5:c.113A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022482.5(GZF1):​c.113A>C​(p.Glu38Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GZF1 NM_022482.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.89
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

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.113A>C	p.Glu38Ala	missense	Exon 2 of 6	NP_071927.1	Q9H116-1
	GZF1	NM_001317012.2		c.113A>C	p.Glu38Ala	missense	Exon 3 of 7	NP_001303941.1	Q9H116-1
	GZF1	NM_001317019.1		c.113A>C	p.Glu38Ala	missense	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.113A>C	p.Glu38Ala	missense	Exon 2 of 6	ENSP00000338290.5	Q9H116-1
	GZF1	ENST00000377051.2	TSL:1	c.113A>C	p.Glu38Ala	missense	Exon 1 of 5	ENSP00000366250.2	Q9H116-1
	GZF1	ENST00000907448.1		c.113A>C	p.Glu38Ala	missense	Exon 2 of 7	ENSP00000577507.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.9	L
PhyloP100		8.9
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.96	D
Vest4		0.59
MutPred		0.74		Loss of phosphorylation at Y39 (P = 0.1011)
MVP		0.83
MPC		1.4
ClinPred		0.91	D
GERP RS		5.2
PromoterAI		0.069	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.52
Mutation Taster		=31/69	disease causing

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: rs1162238866; hg19: chr20-23345133;