dbSNP rs567038987: ZNF469:p.Arg1610His (chr16-88432299-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001367624.2(ZNF469):c.4829G>A(p.Arg1610His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000802 in 1,547,072 control chromosomes in the GnomAD database, with no homozygous occurrence. 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).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

ZNF469
NM_001367624.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.533

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.050953448).

BP6

Variant 16-88432299-G-A is Benign according to our data. Variant chr16-88432299-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 284987.

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.4829G>A	p.Arg1610His	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.4829G>A	p.Arg1610His	missense	Exon 3 of 3	ENSP00000456500.2	Q96JG9
	ZNF469	ENST00000437464.1	TSL:5	c.4745G>A	p.Arg1582His	missense	Exon 2 of 2	ENSP00000402343.1	A0AAA9X9E9

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000108

AC:

AN:

148196

AF XY:

0.000113

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000813

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000466

Gnomad FIN exome

AF:

0.000160

Gnomad NFE exome

AF:

0.000121

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000810

AC:

113

AN:

1394758

Hom.:

Cov.:

AF XY:

0.0000828

AC XY:

AN XY:

688070

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31598

American (AMR)

AF:

0.0000560

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.000224

AC:

AN:

35738

South Asian (SAS)

AF:

0.0000252

AC:

AN:

79230

European-Finnish (FIN)

AF:

0.0000895

AC:

AN:

44714

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000862

AC:

AN:

1078938

Other (OTH)

AF:

0.0000690

AC:

AN:

57960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41572

American (AMR)

AF:

0.0000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.000162

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000434

AC:

Asia WGS

AF:

0.000289

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 (2)

Brittle cornea syndrome 1 (1)

Cardiovascular phenotype (1)

ZNF469-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.78

CADD

Benign

8.5

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.0063

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.46

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.051

MetaSVM

Benign

-0.93

PhyloP100

0.53

PrimateAI

Benign

0.24

PROVEAN

Benign

0.28

REVEL

Benign

0.011

Sift

Benign

0.22

Sift4G

Benign

0.28

Vest4

0.034

MVP

0.13

ClinPred

0.011

GERP RS

0.059

gMVP

0.14

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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