16-88438442-G-C

Variant names:

• chr16-88438442-G-C
• rs1105066
• NM_001367624.2:c.10972G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001367624.2(ZNF469):​c.10972G>C​(p.Glu3658Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,549,886 control chromosomes in the GnomAD database, including 134,381 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E3658A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.43 (14845 hom., cov: 34)
  • Exomes 𝑓: 0.41 (119536 hom.)
• Consequence: ZNF469 NM_001367624.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0480
• Publications: 22 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.0975698E-5).
• BP6: Variant 16-88438442-G-C is Benign according to our data. Variant chr16-88438442-G-C is described in ClinVar as Benign. ClinVar VariationId is 321020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

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.10972G>C	p.Glu3658Gln	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.10972G>C	p.Glu3658Gln	missense	Exon 3 of 3	ENSP00000456500.2
	ZNF469	ENST00000437464.1	TSL:5	c.10888G>C	p.Glu3630Gln	missense	Exon 2 of 2	ENSP00000402343.1

Frequencies

GnomAD3 genomes AF: 0.435 AC: 66044 AN: 151960 Hom.: 14804 Cov.: 34

Gnomad AFR AF: 0.524

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.459

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.359

GnomAD2 exomes AF: 0.373 AC: 54523 AN: 146310 AF XY: 0.364

Gnomad AFR exome AF: 0.529

Gnomad AMR exome AF: 0.318

Gnomad ASJ exome AF: 0.298

Gnomad EAS exome AF: 0.420

Gnomad FIN exome AF: 0.459

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.409 AC: 571778 AN: 1397808 Hom.: 119536 Cov.: 95 AF XY: 0.404 AC XY: 278240 AN XY: 689390

African (AFR) AF: 0.530 AC: 16762 AN: 31598

American (AMR) AF: 0.323 AC: 11545 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 7416 AN: 25180

East Asian (EAS) AF: 0.381 AC: 13610 AN: 35736

South Asian (SAS) AF: 0.236 AC: 18692 AN: 79236

European-Finnish (FIN) AF: 0.455 AC: 21711 AN: 47746

Middle Eastern (MID) AF: 0.248 AC: 1410 AN: 5696

European-Non Finnish (NFE) AF: 0.425 AC: 458546 AN: 1078930

Other (OTH) AF: 0.381 AC: 22086 AN: 57984

GnomAD4 genome AF: 0.435 AC: 66134 AN: 152078 Hom.: 14845 Cov.: 34 AF XY: 0.432 AC XY: 32069 AN XY: 74318

African (AFR) AF: 0.525 AC: 21786 AN: 41490

American (AMR) AF: 0.355 AC: 5431 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 998 AN: 3468

East Asian (EAS) AF: 0.403 AC: 2077 AN: 5150

South Asian (SAS) AF: 0.242 AC: 1167 AN: 4822

European-Finnish (FIN) AF: 0.459 AC: 4861 AN: 10586

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.419 AC: 28483 AN: 67966

Other (OTH) AF: 0.355 AC: 748 AN: 2108

Alfa AF: 0.408 Hom.: 4155

Bravo AF: 0.429

TwinsUK AF: 0.422 AC: 1566

ALSPAC AF: 0.444 AC: 1710

ESP6500AA AF: 0.533 AC: 729

ESP6500EA AF: 0.415 AC: 1311

ExAC AF: 0.315 AC: 6601

Asia WGS AF: 0.328 AC: 1141 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brittle cornea syndrome 1 Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 15, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Sep 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 04, 2018

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Benign	0.51
DEOGEN2	Benign	0.0074	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.000041	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.048
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.040
Sift	Benign	0.043	D
Sift4G	Uncertain	0.022	D
Vest4		0.022
ClinPred		0.0025	T
GERP RS		1.3
gMVP		0.030
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1105066; hg19: chr16-88504850; COSMIC: COSV71258359;