Genetic Variant NM_022482.5:c.9C>A (chr20-23364392-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022482.5(GZF1):c.9C>A(p.Ser3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S3S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GZF1
NM_022482.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.514

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19369209).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GZF1	NM_022482.5 link	c.9C>A	p.Ser3Arg	missense_variant	Exon 2 of 6	ENST00000338121.10	NP_071927.1	Q9H116-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GZF1	ENST00000338121.10 link	c.9C>A	p.Ser3Arg	missense_variant	Exon 2 of 6	1	NM_022482.5	ENSP00000338290.5	Q9H116-1
GZF1	ENST00000377051.2 link	c.9C>A	p.Ser3Arg	missense_variant	Exon 1 of 5	1		ENSP00000366250.2	Q9H116-1
GZF1	ENST00000424216.1 link	c.9C>A	p.Ser3Arg	missense_variant	Exon 3 of 3	5		ENSP00000410009.1	Q5JXG1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1411296

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696238

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

May 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.9C>A (p.S3R) alteration is located in exon 1 (coding exon 1) of the GZF1 gene. This alteration results from a C to A substitution at nucleotide position 9, causing the serine (S) at amino acid position 3 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

T;.;T

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.79

.;T;T

M_CAP

Benign

0.038

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

2.0

M;.;M

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.2

N;D;N

REVEL

Benign

0.13

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

0.99

D;.;D

Vest4

0.36

MutPred

0.19

Loss of phosphorylation at S3 (P = 0.0228);Loss of phosphorylation at S3 (P = 0.0228);Loss of phosphorylation at S3 (P = 0.0228);

MVP

0.27

MPC

1.4

ClinPred

0.81

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over