rs116532825

chr16-88431833-C-Gchr16-88431833-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001367624.2(ZNF469):c.4363C>G(p.Leu1455Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,549,822 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1455L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0082 (19 hom., cov: 34)
  • Exomes 𝑓: 0.00083 (18 hom.)
• Consequence: ZNF469 NM_001367624.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.40

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00415045).
• BP6: Variant 16-88431833-C-G is Benign according to our data. Variant chr16-88431833-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 320920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88431833-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00823 (1253/152328) while in subpopulation AFR AF= 0.0282 (1173/41568). AF 95% confidence interval is 0.0269. There are 19 homozygotes in gnomad4. There are 591 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF469	NM_001367624.2	c.4363C>G	p.Leu1455Val	missense_variant	3/3	ENST00000565624.3
ZNF469	XM_047434810.1	c.4363C>G	p.Leu1455Val	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF469	ENST00000565624.3	c.4363C>G	p.Leu1455Val	missense_variant	3/3		NM_001367624.2	A2
ZNF469	ENST00000437464.1	c.4279C>G	p.Leu1427Val	missense_variant	2/2	5		P4

Frequencies

GnomAD3 genomes AF: 0.00817 AC: 1244 AN: 152210 Hom.: 18 Cov.: 34

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00186 AC: 285 AN: 153314 Hom.: 2 AF XY: 0.00145 AC XY: 118 AN XY: 81502

Gnomad AFR exome AF: 0.0294

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000168

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000825 AC: 1153 AN: 1397494 Hom.: 18 Cov.: 86 AF XY: 0.000712 AC XY: 491 AN XY: 689248

Gnomad4 AFR exome AF: 0.0285

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000213

Gnomad4 OTH exome AF: 0.00241

GnomAD4 genome AF: 0.00823 AC: 1253 AN: 152328 Hom.: 19 Cov.: 34 AF XY: 0.00793 AC XY: 591 AN XY: 74482

Gnomad4 AFR AF: 0.0282

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000404 Hom.: 0

Bravo AF: 0.00967

ExAC AF: 0.00318 AC: 71

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 02, 2017	- -

Brittle cornea syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 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	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.53	T;.
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N;N
Sift	Uncertain	0.018	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.17
MVP		0.46
ClinPred		0.016	T
GERP RS		2.7
gMVP		0.046

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

Other links and lift over

dbSNP: rs116532825; hg19: chr16-88498241; COSMIC: COSV99081568;