16-88429877-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001367624.2(ZNF469):c.2407G>T(p.Ala803Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,550,118 control chromosomes in the GnomAD database, including 68 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. A803T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 35 hom., cov: 34)

Exomes 𝑓: 0.0013 ( 33 hom. )

Consequence

ZNF469
NM_001367624.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.152

Publications

2 publications found

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 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

ZNF469 links:

LOC112268182 (HGNC:):

LOC112268182 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0019454062).

BP6

Variant 16-88429877-G-T is Benign according to our data. Variant chr16-88429877-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 320886.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 = 0.0117 (1782/152300) while in subpopulation AFR AF = 0.0397 (1649/41552). AF 95% confidence interval is 0.0381. There are 35 homozygotes in GnomAd4. There are 853 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ZNF469	NM_001367624.2 link	c.2407G>T	p.Ala803Ser	missense_variant	Exon 3 of 3	ENST00000565624.3	NP_001354553.1
ZNF469	XM_047434810.1 link	c.2407G>T	p.Ala803Ser	missense_variant	Exon 4 of 4		XP_047290766.1
LOC112268182	XR_007065178.1 link	n.250+87C>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF469	ENST00000565624.3 link	c.2407G>T	p.Ala803Ser	missense_variant	Exon 3 of 3	6	NM_001367624.2	ENSP00000456500.2		H3BS19
ZNF469	ENST00000437464.1 link	c.2407G>T	p.Ala803Ser	missense_variant	Exon 1 of 2	5		ENSP00000402343.1		Q96JG9

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1776

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0397

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00654

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:

0.000250

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00255

AC:

383

AN:

150372

AF XY:

0.00192

show subpopulations

Gnomad AFR exome

AF:

0.0364

Gnomad AMR exome

AF:

0.00366

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000263

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00133

AC:

1857

AN:

1397818

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

842

AN XY:

689410

show subpopulations

African (AFR)

AF:

0.0430

AC:

1358

AN:

31594

American (AMR)

AF:

0.00331

AC:

118

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25170

East Asian (EAS)

AF:

0.00

AC:

AN:

35732

South Asian (SAS)

AF:

0.000164

AC:

AN:

79226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47862

Middle Eastern (MID)

AF:

0.00649

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.000106

AC:

114

AN:

1078858

Other (OTH)

AF:

0.00374

AC:

217

AN:

57976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

134

268

401

535

669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0117

AC:

1782

AN:

152300

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

853

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0397

AC:

1649

AN:

41552

American (AMR)

AF:

0.00653

AC:

100

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68018

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

160

239

319

399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00671

Hom.:

Bravo

AF:

0.0129

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00293

AC:

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: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

- -

Dec 30, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 11, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brittle cornea syndrome 1

Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely 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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.046

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.0018

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.20

T;.

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.93

PhyloP100

-0.15

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.010

N;N

REVEL

Benign

0.029

Sift

Benign

0.85

T;T

Sift4G

Benign

0.13

T;T

Vest4

0.061

MVP

0.12

ClinPred

0.0012

GERP RS

-6.2

gMVP

0.039

Mutation Taster

=94/6

polymorphism

(source)

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

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16-88429877-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over