rs200668806

Positions:

chr16-88438358-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001367624.2(ZNF469):c.10888C>T(p.Arg3630Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,550,196 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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 0.0018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0032 ( 12 hom. )

Consequence

ZNF469
NM_001367624.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 1.06

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023705363).

BP6

Variant 16-88438358-C-T is Benign according to our data. Variant chr16-88438358-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421677.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=5}. Variant chr16-88438358-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00179 (273/152286) while in subpopulation NFE AF= 0.00329 (224/68016). AF 95% confidence interval is 0.00294. There are 0 homozygotes in gnomad4. There are 139 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF469	NM_001367624.2 link	c.10888C>T	p.Arg3630Cys	missense_variant	3/3	ENST00000565624.3	NP_001354553.1
ZNF469	XM_047434810.1 link	c.10888C>T	p.Arg3630Cys	missense_variant	4/4		XP_047290766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF469	ENST00000565624.3 link	c.10888C>T	p.Arg3630Cys	missense_variant	3/3	6	NM_001367624.2	ENSP00000456500.2		H3BS19
ZNF469	ENST00000437464.1 link	c.10804C>T	p.Arg3602Cys	missense_variant	2/2	5		ENSP00000402343.1		Q96JG9

Frequencies

GnomAD3 genomes

AF:

0.00179

AC:

273

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00329

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00152

AC:

226

AN:

149024

Hom.:

AF XY:

0.00141

AC XY:

113

AN XY:

80036

show subpopulations

Gnomad AFR exome

AF:

0.000986

Gnomad AMR exome

AF:

0.000651

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000440

Gnomad FIN exome

AF:

0.000131

Gnomad NFE exome

AF:

0.00339

Gnomad OTH exome

AF:

0.00235

GnomAD4 exome

AF:

0.00322

AC:

4498

AN:

1397910

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

2139

AN XY:

689446

show subpopulations

Gnomad4 AFR exome

AF:

0.000665

Gnomad4 AMR exome

AF:

0.000756

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000505

Gnomad4 FIN exome

AF:

0.000230

Gnomad4 NFE exome

AF:

0.00390

Gnomad4 OTH exome

AF:

0.00398

GnomAD4 genome

AF:

0.00179

AC:

273

AN:

152286

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

139

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00329

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00243

Hom.:

Bravo

AF:

0.00193

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ExAC

AF:

0.00111

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ZNF469: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2021	This variant is associated with the following publications: (PMID: 24895405) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Brittle cornea syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Ehlers-Danlos syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2022

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2019

This alteration is classified as likely 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

0.15

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.30

DEOGEN2

Benign

0.0054

T;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.56

T;.

M_CAP

Pathogenic

0.83

MetaRNN

Benign

0.024

T;T

MetaSVM

Benign

-0.99

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.74

N;N

REVEL

Benign

0.057

Sift

Benign

0.098

T;T

Sift4G

Benign

0.10

T;T

Vest4

0.14

MVP

0.27

ClinPred

0.018

GERP RS

2.2

gMVP

0.022

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over