Genetic Variant GZF1:p.Glu38Gly (chr20-23364496-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022482.5(GZF1):c.113A>G(p.Glu38Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E38A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GZF1
NM_022482.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.89

Publications

0 publications found

Variant links:

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

GZF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GZF1	NM_022482.5	MANE Select	c.113A>G	p.Glu38Gly	missense	Exon 2 of 6	NP_071927.1	Q9H116-1
GZF1	NM_001317012.2		c.113A>G	p.Glu38Gly	missense	Exon 3 of 7	NP_001303941.1	Q9H116-1
GZF1	NM_001317019.1		c.113A>G	p.Glu38Gly	missense	Exon 1 of 5	NP_001303948.1	Q9H116

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GZF1	ENST00000338121.10	TSL:1 MANE Select	c.113A>G	p.Glu38Gly	missense	Exon 2 of 6	ENSP00000338290.5	Q9H116-1
GZF1	ENST00000377051.2	TSL:1	c.113A>G	p.Glu38Gly	missense	Exon 1 of 5	ENSP00000366250.2	Q9H116-1
GZF1	ENST00000907448.1		c.113A>G	p.Glu38Gly	missense	Exon 2 of 7	ENSP00000577507.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251474

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.75

M_CAP

Uncertain

0.090

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.78

PhyloP100

8.9

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.40

Sift

Uncertain

0.0040

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.62

MutPred

0.69

Loss of stability (P = 0.0546)

MVP

0.80

MPC

1.5

ClinPred

0.66

GERP RS

5.2

PromoterAI

0.00060

Neutral

(source)

Varity_R

0.21

gMVP

0.58

Mutation Taster

=31/69

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over