rs773925755

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001367624.2(ZNF469):c.4952A>G(p.Gln1651Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000366 in 1,550,174 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q1651Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00037 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00037 ( 1 hom. )

Consequence

ZNF469
NM_001367624.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: -0.724

Publications

1 publications found

Variant links:

Genes affected

ZNF469 (HGNC:23216): (zinc finger protein 469) This gene encodes a zinc-finger protein. Low-percent homology to certain collagens suggests that it may function as a transcription factor or extra-nuclear regulator factor for the synthesis or organization of collagen fibers. Mutations in this gene cause brittle cornea syndrome. [provided by RefSeq, Jul 2008]

ZNF469 Gene-Disease associations (from GenCC):

brittle cornea syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
brittle cornea syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
aortic disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ZNF469 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018613935).

BP6

Variant 16-88432422-A-G is Benign according to our data. Variant chr16-88432422-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195119.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000368 (56/152350) while in subpopulation AMR AF = 0.00124 (19/15306). AF 95% confidence interval is 0.000812. There are 1 homozygotes in GnomAd4. There are 23 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_001367624.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF469	NM_001367624.2	MANE Select	c.4952A>G	p.Gln1651Arg	missense	Exon 3 of 3	NP_001354553.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF469	ENST00000565624.3	TSL:6 MANE Select	c.4952A>G	p.Gln1651Arg	missense	Exon 3 of 3	ENSP00000456500.2
	ZNF469	ENST00000437464.1	TSL:5	c.4868A>G	p.Gln1623Arg	missense	Exon 2 of 2	ENSP00000402343.1

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000454

AC:

AN:

152026

AF XY:

0.000444

show subpopulations

Gnomad AFR exome

AF:

0.000267

Gnomad AMR exome

AF:

0.000730

Gnomad ASJ exome

AF:

0.00190

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000394

Gnomad OTH exome

AF:

0.00162

GnomAD4 exome

AF:

0.000366

AC:

512

AN:

1397824

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

250

AN XY:

689432

show subpopulations

African (AFR)

AF:

0.000222

AC:

AN:

31598

American (AMR)

AF:

0.000672

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00306

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.000177

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47752

Middle Eastern (MID)

AF:

0.00772

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.000260

AC:

281

AN:

1078940

Other (OTH)

AF:

0.00112

AC:

AN:

57980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

120

160

200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000368

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41594

American (AMR)

AF:

0.00124

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000447

Hom.:

Bravo

AF:

0.000412

ExAC

AF:

0.000360

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ZNF469: BP4

Apr 02, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 01, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28377322)

Aug 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1623 of the ZNF469 protein (p.Gln1623Arg). This variant is present in population databases (rs773925755, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with ZNF469-related conditions. ClinVar contains an entry for this variant (Variation ID: 195119). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

Ehlers-Danlos syndrome

Uncertain:1

Jan 17, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Brittle cornea syndrome 1

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Aug 26, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.017

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.011

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.35

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.94

PhyloP100

-0.72

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.28

REVEL

Benign

0.0040

Sift

Benign

0.49

Sift4G

Benign

0.21

Vest4

0.029

MVP

0.16

ClinPred

0.0014

GERP RS

-8.4

gMVP

0.24

Mutation Taster

=99/1

polymorphism

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over