rs773925755

chr16-88432422-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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. 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). 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: -0.724

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 195119.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3}. Variant chr16-88432422-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000366 (512/1397824) while in subpopulation MID AF= 0.00772 (44/5698). AF 95% confidence interval is 0.00591. There are 1 homozygotes in gnomad4_exome. There are 250 alleles in male gnomad4_exome subpopulation. Median coverage is 96. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF469	NM_001367624.2	c.4952A>G	p.Gln1651Arg	missense_variant	3/3	ENST00000565624.3
ZNF469	XM_047434810.1	c.4952A>G	p.Gln1651Arg	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF469	ENST00000565624.3	c.4952A>G	p.Gln1651Arg	missense_variant	3/3		NM_001367624.2	A2
ZNF469	ENST00000437464.1	c.4868A>G	p.Gln1623Arg	missense_variant	2/2	5		P4

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152232 Hom.: 1 Cov.: 33

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

GnomAD3 exomes AF: 0.000454 AC: 69 AN: 152026 Hom.: 0 AF XY: 0.000444 AC XY: 36 AN XY: 81138

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 SAS exome AF: 0.000132

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.: 1 Cov.: 96 AF XY: 0.000363 AC XY: 250 AN XY: 689432

Gnomad4 AFR exome AF: 0.000222

Gnomad4 AMR exome AF: 0.000672

Gnomad4 ASJ exome AF: 0.00306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000177

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000260

Gnomad4 OTH exome AF: 0.00112

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74504

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000447 Hom.: 0

Bravo AF: 0.000412

ExAC AF: 0.000360 AC: 9

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ZNF469: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2021	This variant is associated with the following publications: (PMID: 28377322) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 02, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2022	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

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 17, 2022

- -

Brittle cornea syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2021

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.017
Dann	Benign	0.44
DEOGEN2	Benign	0.011	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.35	T;.
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.019	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.28	N;N
Sift	Benign	0.49	T;T
Sift4G	Benign	0.21	T;T
Vest4		0.029
MVP		0.16
ClinPred		0.0014	T
GERP RS		-8.4
gMVP		0.24

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

Other links and lift over

dbSNP: rs773925755; hg19: chr16-88498830;