20-23364431-C-A

Position:

• chr20-23364431-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022482.5(GZF1):​c.48C>A​(p.Asn16Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: 2.02

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35492116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GZF1	NM_022482.5	c.48C>A	p.Asn16Lys	missense_variant	2/6	ENST00000338121.10	NP_071927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GZF1	ENST00000338121.10	c.48C>A	p.Asn16Lys	missense_variant	2/6	1	NM_022482.5	ENSP00000338290.5
GZF1	ENST00000377051.2	c.48C>A	p.Asn16Lys	missense_variant	1/5	1		ENSP00000366250.2
GZF1	ENST00000424216.1	c.48C>A	p.Asn16Lys	missense_variant	3/3	5		ENSP00000410009.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 01, 2023

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 16 of the GZF1 protein (p.Asn16Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GZF1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.76
DEOGEN2	Benign	0.055	T;.;T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.69	.;T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.2	L;.;L
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0070	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.97	D;.;D
Vest4		0.58
MutPred		0.40		Gain of methylation at N16 (P = 0.0072);Gain of methylation at N16 (P = 0.0072);Gain of methylation at N16 (P = 0.0072);
MVP		0.78
MPC		1.4
ClinPred		0.85	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-23345068;