16-88430187-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001367624.2(ZNF469):c.2717C>T(p.Pro906Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00701 in 1,547,798 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. P906P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0050 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0072 ( 49 hom. )

Consequence

ZNF469
NM_001367624.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: -1.12

Publications

7 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0147075355).

BP6

Variant 16-88430187-C-T is Benign according to our data. Variant chr16-88430187-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193172.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00501 (764/152344) while in subpopulation NFE AF = 0.00785 (534/68028). AF 95% confidence interval is 0.0073. There are 1 homozygotes in GnomAd4. There are 356 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 49 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF469	NM_001367624.2	MANE Select	c.2717C>T	p.Pro906Leu	missense	Exon 3 of 3	NP_001354553.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF469	ENST00000565624.3	TSL:6 MANE Select	c.2717C>T	p.Pro906Leu	missense	Exon 3 of 3	ENSP00000456500.2
	ZNF469	ENST00000437464.1	TSL:5	c.2717C>T	p.Pro906Leu	missense	Exon 1 of 2	ENSP00000402343.1

Frequencies

GnomAD3 genomes

AF:

0.00502

AC:

764

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00393

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00508

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00785

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00382

AC:

551

AN:

144094

AF XY:

0.00376

show subpopulations

Gnomad AFR exome

AF:

0.00169

Gnomad AMR exome

AF:

0.000369

Gnomad ASJ exome

AF:

0.000366

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00420

Gnomad NFE exome

AF:

0.00864

Gnomad OTH exome

AF:

0.00168

GnomAD4 exome

AF:

0.00723

AC:

10093

AN:

1395454

Hom.:

Cov.:

AF XY:

0.00702

AC XY:

4827

AN XY:

687890

show subpopulations

African (AFR)

AF:

0.00317

AC:

100

AN:

31548

American (AMR)

AF:

0.000533

AC:

AN:

35670

Ashkenazi Jewish (ASJ)

AF:

0.000279

AC:

AN:

25126

East Asian (EAS)

AF:

0.00

AC:

AN:

35696

South Asian (SAS)

AF:

0.0000253

AC:

AN:

79200

European-Finnish (FIN)

AF:

0.00559

AC:

264

AN:

47232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00881

AC:

9491

AN:

1077388

Other (OTH)

AF:

0.00363

AC:

210

AN:

57912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

615

1230

1845

2460

3075

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

374

748

1122

1496

1870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00501

AC:

764

AN:

152344

Hom.:

Cov.:

AF XY:

0.00478

AC XY:

356

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00392

AC:

163

AN:

41586

American (AMR)

AF:

0.000784

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00508

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00785

AC:

534

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00692

Hom.:

Bravo

AF:

0.00433

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00519

AC:

ExAC

AF:

0.00143

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Brittle cornea syndrome 1 (2)

not specified (2)

Cardiovascular phenotype (1)

Ehlers-Danlos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.26

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.016

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.43

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.96

PhyloP100

-1.1

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.8

REVEL

Benign

0.032

Sift

Benign

0.092

Sift4G

Uncertain

0.0090

Vest4

0.17

MVP

0.23

ClinPred

0.0012

GERP RS

-0.48

gMVP

0.057

Mutation Taster

=95/5

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over