chr16-88429877-G-T

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

17

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

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 UniProt
ZNF469NM_001367624.2 linkc.2407G>T p.Ala803Ser missense_variant Exon 3 of 3 ENST00000565624.3 NP_001354553.1
ZNF469XM_047434810.1 linkc.2407G>T p.Ala803Ser missense_variant Exon 4 of 4 XP_047290766.1
LOC112268182XR_007065178.1 linkn.250+87C>A intron_variant Intron 2 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZNF469ENST00000565624.3 linkc.2407G>T p.Ala803Ser missense_variant Exon 3 of 3 6 NM_001367624.2 ENSP00000456500.2 H3BS19
ZNF469ENST00000437464.1 linkc.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.:
36
Cov.:
34
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.:
33
Cov.:
65
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:
0
AN:
25170
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35732
South Asian (SAS)
AF:
0.000164
AC:
13
AN:
79226
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
47862
Middle Eastern (MID)
AF:
0.00649
AC:
37
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
0
134
268
401
535
669
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
48
96
144
192
240
<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:
0.0117
AC:
1782
AN:
152300
Hom.:
35
Cov.:
34
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:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5170
South Asian (SAS)
AF:
0.000414
AC:
2
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.0102
AC:
3
AN:
294
European-Non Finnish (NFE)
AF:
0.000250
AC:
17
AN:
68018
Other (OTH)
AF:
0.00520
AC:
11
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
80
160
239
319
399
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
20
40
60
80
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:
0.00671
Hom.:
6
Bravo
AF:
0.0129
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.00293
AC:
76
Asia WGS
AF:
0.00462
AC:
16
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
T
BayesDel_noAF
Benign
-0.81
CADD
Benign
0.046
DANN
Benign
0.63
DEOGEN2
Benign
0.0018
T;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.20
T;.
MetaRNN
Benign
0.0019
T;T
MetaSVM
Benign
-0.93
T
PhyloP100
-0.15
PrimateAI
Benign
0.33
T
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
T
GERP RS
-6.2
gMVP
0.039
Mutation Taster
=94/6
polymorphism

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

Other links and lift over

dbSNP: rs113484918; hg19: chr16-88496285; API