rs766410344

Positions:

chr16-88433384-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001367624.2(ZNF469):c.5914G>A(p.Gly1972Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,550,218 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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. G1972V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

ZNF469
NM_001367624.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: -0.986

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.011570811).

BP6

Variant 16-88433384-G-A is Benign according to our data. Variant chr16-88433384-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 373813.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF469	NM_001367624.2 linkuse as main transcript	c.5914G>A	p.Gly1972Arg	missense_variant	3/3	ENST00000565624.3
ZNF469	XM_047434810.1 linkuse as main transcript	c.5914G>A	p.Gly1972Arg	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF469	ENST00000565624.3 linkuse as main transcript	c.5914G>A	p.Gly1972Arg	missense_variant	3/3		NM_001367624.2	A2
ZNF469	ENST00000437464.1 linkuse as main transcript	c.5830G>A	p.Gly1944Arg	missense_variant	2/2	5		P4

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000359

AC:

AN:

153108

Hom.:

AF XY:

0.000356

AC XY:

AN XY:

81518

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.0000811

Gnomad ASJ exome

AF:

0.00520

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000119

Gnomad OTH exome

AF:

0.000231

GnomAD4 exome

AF:

0.000174

AC:

243

AN:

1398016

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

137

AN XY:

689502

show subpopulations

Gnomad4 AFR exome

AF:

0.0000949

Gnomad4 AMR exome

AF:

0.0000560

Gnomad4 ASJ exome

AF:

0.00544

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000209

Gnomad4 NFE exome

AF:

0.0000723

Gnomad4 OTH exome

AF:

0.000379

GnomAD4 genome

AF:

0.000184

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000576

Hom.:

Bravo

AF:

0.000223

ExAC

AF:

0.000726

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ZNF469: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 15, 2016

A variant of uncertain significance has been identified in the ZNF469 gene. The G1944R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 2,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, but was observed in 17/7004 (0.24%) alleles from individuals of Non-Finnish European ancestry in the Exome Aggregation Consortium. The G1944R 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. However, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -

Brittle cornea syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Ehlers-Danlos syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 23, 2020

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2020

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. -

ZNF469-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2019

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

0.10

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.0060

DANN

Benign

0.29

DEOGEN2

Benign

0.0056

T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.48

T;.

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

0.31

N;N

REVEL

Benign

0.0020

Sift

Benign

0.87

T;T

Sift4G

Benign

0.95

T;T

Vest4

0.084

MutPred

0.27

.;Loss of catalytic residue at A1943 (P = 0.027);

MVP

0.14

ClinPred

0.0021

GERP RS

-2.9

gMVP

0.15

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

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