rs773925755

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001367624.2(ZNF469):c.4952A>G(p.Gln1651Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000366 in 1,550,174 control chromosomes in the GnomAD database, including 2 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. Q1651Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00037 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00037 ( 1 hom. )

Consequence

ZNF469
NM_001367624.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: -0.724

Publications

1 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
brittle cornea syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
aortic disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ZNF469 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018613935).

BP6

Variant 16-88432422-A-G is Benign according to our data. Variant chr16-88432422-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195119.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000368 (56/152350) while in subpopulation AMR AF = 0.00124 (19/15306). AF 95% confidence interval is 0.000812. There are 1 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.4952A>G	p.Gln1651Arg	missense	Exon 3 of 3	NP_001354553.1	Q96JG9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF469	ENST00000565624.3	TSL:6 MANE Select	c.4952A>G	p.Gln1651Arg	missense	Exon 3 of 3	ENSP00000456500.2	Q96JG9
	ZNF469	ENST00000437464.1	TSL:5	c.4868A>G	p.Gln1623Arg	missense	Exon 2 of 2	ENSP00000402343.1	A0AAA9X9E9

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000454

AC:

AN:

152026

AF XY:

0.000444

show subpopulations

Gnomad AFR exome

AF:

0.000267

Gnomad AMR exome

AF:

0.000730

Gnomad ASJ exome

AF:

0.00190

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000394

Gnomad OTH exome

AF:

0.00162

GnomAD4 exome

AF:

0.000366

AC:

512

AN:

1397824

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

250

AN XY:

689432

show subpopulations

African (AFR)

AF:

0.000222

AC:

AN:

31598

American (AMR)

AF:

0.000672

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00306

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.000177

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47752

Middle Eastern (MID)

AF:

0.00772

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.000260

AC:

281

AN:

1078940

Other (OTH)

AF:

0.00112

AC:

AN:

57980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

120

160

200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000368

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41594

American (AMR)

AF:

0.00124

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000447

Hom.:

Bravo

AF:

0.000412

ExAC

AF:

0.000360

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Brittle cornea syndrome 1 (1)

Cardiovascular phenotype (1)

Ehlers-Danlos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.017

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.011

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.35

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.94

PhyloP100

-0.72

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.28

REVEL

Benign

0.0040

Sift

Benign

0.49

Sift4G

Benign

0.21

Vest4

0.029

MVP

0.16

ClinPred

0.0014

GERP RS

-8.4

gMVP

0.24

Mutation Taster

=99/1

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