16-88432557-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.5087C>T(p.Pro1696Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,550,408 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (19 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (19 hom.)
• Consequence: ZNF469 NM_001367624.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.436

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=0.0028225482).
• BP6: Variant 16-88432557-C-T is Benign according to our data. Variant chr16-88432557-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 320936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88432557-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00817 (1245/152324) while in subpopulation AFR AF= 0.0281 (1168/41560). AF 95% confidence interval is 0.0268. There are 19 homozygotes in gnomad4. There are 585 alleles in male gnomad4 subpopulation. Median coverage is 33. 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.5087C>T	p.Pro1696Leu	missense_variant	3/3	ENST00000565624.3
ZNF469	XM_047434810.1	c.5087C>T	p.Pro1696Leu	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF469	ENST00000565624.3	c.5087C>T	p.Pro1696Leu	missense_variant	3/3		NM_001367624.2	A2
ZNF469	ENST00000437464.1	c.5003C>T	p.Pro1668Leu	missense_variant	2/2	5		P4

Frequencies

GnomAD3 genomes AF: 0.00813 AC: 1237 AN: 152206 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

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: 0.000147

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00185 AC: 285 AN: 153836 Hom.: 3 AF XY: 0.00146 AC XY: 119 AN XY: 81718

Gnomad AFR exome AF: 0.0295

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: 0.00

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000820 AC: 1146 AN: 1398084 Hom.: 19 Cov.: 96 AF XY: 0.000709 AC XY: 489 AN XY: 689530

Gnomad4 AFR exome AF: 0.0284

Gnomad4 AMR exome AF: 0.00227

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: 0.0000148

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00817 AC: 1245 AN: 152324 Hom.: 19 Cov.: 33 AF XY: 0.00785 AC XY: 585 AN XY: 74506

Gnomad4 AFR AF: 0.0281

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00140 Hom.: 2

Bravo AF: 0.00964

ESP6500AA AF: 0.0275 AC: 38

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00308 AC: 72

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:2

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	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 04, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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	0.097
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.97
Dann	Benign	0.44
DEOGEN2	Benign	0.010	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.49	T;.
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.15	N;N
Sift	Benign	0.27	T;T
Sift4G	Benign	0.42	T;T
Vest4		0.056
MVP		0.19
ClinPred		0.00030	T
GERP RS		-2.0
gMVP		0.067

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: rs115487796; hg19: chr16-88498965; COSMIC: COSV99081569;