16-88430136-C-T

Variant names:

• chr16-88430136-C-T
• rs145186655
• NM_001367624.2:c.2666C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001367624.2(ZNF469):​c.2666C>T​(p.Ala889Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,550,136 control chromosomes in the GnomAD database, including 46 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A889T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (23 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: ZNF469 NM_001367624.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0840
• Publications: 1 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

LOC112268182 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016812086).
• BP6: Variant 16-88430136-C-T is Benign according to our data. Variant chr16-88430136-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 320889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.01 (1530/152260) while in subpopulation AFR AF = 0.0341 (1417/41530). AF 95% confidence interval is 0.0326. There are 23 homozygotes in GnomAd4. There are 717 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR,AD gene

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.2666C>T	p.Ala889Val	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.2666C>T	p.Ala889Val	missense	Exon 3 of 3	ENSP00000456500.2
	ZNF469	ENST00000437464.1	TSL:5	c.2666C>T	p.Ala889Val	missense	Exon 1 of 2	ENSP00000402343.1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1526 AN: 152142 Hom.: 24 Cov.: 34

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00225 AC: 334 AN: 148484 AF XY: 0.00174

Gnomad AFR exome AF: 0.0334

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000269

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00112 AC: 1572 AN: 1397876 Hom.: 23 Cov.: 65 AF XY: 0.00103 AC XY: 711 AN XY: 689438

African (AFR) AF: 0.0364 AC: 1151 AN: 31594

American (AMR) AF: 0.00300 AC: 107 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.000101 AC: 8 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47886

Middle Eastern (MID) AF: 0.00474 AC: 27 AN: 5696

European-Non Finnish (NFE) AF: 0.0000936 AC: 101 AN: 1078876

Other (OTH) AF: 0.00307 AC: 178 AN: 57976

GnomAD4 genome AF: 0.0100 AC: 1530 AN: 152260 Hom.: 23 Cov.: 34 AF XY: 0.00963 AC XY: 717 AN XY: 74476

African (AFR) AF: 0.0341 AC: 1417 AN: 41530

American (AMR) AF: 0.00582 AC: 89 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68018

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00204 Hom.: 9

Bravo AF: 0.0111

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00237 AC: 52

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Mar 11, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 30, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Brittle cornea syndrome 1 Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ehlers-Danlos syndrome Benign:1

Jun 13, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

May 15, 2019

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	0.10
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.46
DANN	Benign	0.83
DEOGEN2	Benign	0.0017	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.084
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.69	N
REVEL	Benign	0.036
Sift	Benign	1.0	T
Sift4G	Benign	0.51	T
Vest4		0.019
MVP		0.12
ClinPred		0.0016	T
GERP RS		-4.2
gMVP		0.054
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs145186655; hg19: chr16-88496544;