16-88437800-G-C

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.10330G>C(p.Gly3444Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000245 in 1,545,660 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3444A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

ZNF469
NM_001367624.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.36

Publications

0 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=0.009708345).

BP6

Variant 16-88437800-G-C is Benign according to our data. Variant chr16-88437800-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 321014.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00129 (197/152342) while in subpopulation AFR AF = 0.0044 (183/41592). AF 95% confidence interval is 0.00388. There are 1 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF469	NM_001367624.2 link	c.10330G>C	p.Gly3444Arg	missense_variant	Exon 3 of 3	ENST00000565624.3	NP_001354553.1
ZNF469	XM_047434810.1 link	c.10330G>C	p.Gly3444Arg	missense_variant	Exon 4 of 4		XP_047290766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF469	ENST00000565624.3 link	c.10330G>C	p.Gly3444Arg	missense_variant	Exon 3 of 3	6	NM_001367624.2	ENSP00000456500.2		H3BS19
ZNF469	ENST00000437464.1 link	c.10246G>C	p.Gly3416Arg	missense_variant	Exon 2 of 2	5		ENSP00000402343.1		Q96JG9

Frequencies

GnomAD3 genomes

AF:

0.00129

AC:

197

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00441

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

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:

0.0000147

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000270

AC:

AN:

144254

AF XY:

0.000218

show subpopulations

Gnomad AFR exome

AF:

0.00388

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000239

GnomAD4 exome

AF:

0.000130

AC:

181

AN:

1393318

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

686294

show subpopulations

African (AFR)

AF:

0.00464

AC:

146

AN:

31472

American (AMR)

AF:

0.000338

AC:

AN:

35522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25102

East Asian (EAS)

AF:

0.00

AC:

AN:

35554

South Asian (SAS)

AF:

0.00

AC:

AN:

79132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47752

Middle Eastern (MID)

AF:

0.000352

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

9.30e-7

AC:

AN:

1075414

Other (OTH)

AF:

0.000347

AC:

AN:

57682

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.00129

AC:

197

AN:

152342

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00440

AC:

183

AN:

41592

American (AMR)

AF:

0.000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000504

Hom.:

Bravo

AF:

0.00163

ExAC

AF:

0.000275

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Brittle cornea syndrome 1

Uncertain:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Dec 17, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ZNF469 c.10330G>C (p.Gly3444Arg) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 144254 control chromosomes, predominantly at a frequency of 0.0039 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in ZNF469 causing Brittle cornea syndrome 1 phenotype. To our knowledge, no occurrence of c.10330G>C in individuals affected with Brittle cornea syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 321014). Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 27, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A variant of uncertain significance has been identified in the ZNF469 gene. The G3416R variant has not been published as pathogenic or been reported as benign to our knowledge. The G3416R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Additionally, G3416R has been observed in 2/166 (1.2%) alleles from individuals of Latino ancestry and in 2/596 (0.3%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015). -

not provided

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Apr 13, 2023

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

ZNF469-related disorder

Benign:1

Feb 20, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.10

T;.

Eigen

Benign

-0.089

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.68

T;.

MetaRNN

Benign

0.0097

T;T

MetaSVM

Benign

-1.1

PhyloP100

4.4

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.5

N;D

REVEL

Benign

0.14

Sift

Uncertain

0.015

D;D

Sift4G

Uncertain

0.0030

D;D

Vest4

0.20

MutPred

0.49

.;Gain of solvent accessibility (P = 0.0037);

MVP

0.21

ClinPred

0.059

GERP RS

3.1

gMVP

0.28

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over