rs77490207

chr16-88434414-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001367624.2(ZNF469):c.6944C>G(p.Pro2315Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,549,764 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (70 hom., cov: 34)
  • Exomes 𝑓: 0.0016 (66 hom.)
• Consequence: ZNF469 NM_001367624.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.314

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026768148).
• BP6: Variant 16-88434414-C-G is Benign according to our data. Variant chr16-88434414-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 320962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88434414-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF469	NM_001367624.2	c.6944C>G	p.Pro2315Arg	missense_variant	3/3	ENST00000565624.3
ZNF469	XM_047434810.1	c.6944C>G	p.Pro2315Arg	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF469	ENST00000565624.3	c.6944C>G	p.Pro2315Arg	missense_variant	3/3		NM_001367624.2	A2
ZNF469	ENST00000437464.1	c.6860C>G	p.Pro2287Arg	missense_variant	2/2	5		P4

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2510 AN: 152200 Hom.: 69 Cov.: 34

Gnomad AFR AF: 0.0573

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00378 AC: 567 AN: 149838 Hom.: 20 AF XY: 0.00288 AC XY: 232 AN XY: 80506

Gnomad AFR exome AF: 0.0620

Gnomad AMR exome AF: 0.00422

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000880

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000175

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.00164 AC: 2291 AN: 1397446 Hom.: 66 Cov.: 98 AF XY: 0.00141 AC XY: 973 AN XY: 689270

Gnomad4 AFR exome AF: 0.0574

Gnomad4 AMR exome AF: 0.00454

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000505

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000436

Gnomad4 OTH exome AF: 0.00431

GnomAD4 genome AF: 0.0165 AC: 2518 AN: 152318 Hom.: 70 Cov.: 34 AF XY: 0.0161 AC XY: 1198 AN XY: 74486

Gnomad4 AFR AF: 0.0573

Gnomad4 AMR AF: 0.00627

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00512 Hom.: 3

Bravo AF: 0.0191

ExAC AF: 0.00461 AC: 116

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Brittle cornea syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 19, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	13
Dann	Benign	0.55
DEOGEN2	Benign	0.023	T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.47	T;.
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.6	N;N
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.028	D;D
Vest4		0.18
MVP		0.44
ClinPred		0.0053	T
GERP RS		2.4
gMVP		0.061

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: rs77490207; hg19: chr16-88500822; COSMIC: COSV99081570;