rs536725615

chr16-88436175-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001367624.2(ZNF469):c.8705C>T(p.Thr2902Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,547,710 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T2902T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0015 (0 hom.)
• Consequence: ZNF469 NM_001367624.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -0.335

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036779344).
• BP6: Variant 16-88436175-C-T is Benign according to our data. Variant chr16-88436175-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 429662.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}. Variant chr16-88436175-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF469	NM_001367624.2	c.8705C>T	p.Thr2902Met	missense_variant	3/3	ENST00000565624.3
ZNF469	XM_047434810.1	c.8705C>T	p.Thr2902Met	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF469	ENST00000565624.3	c.8705C>T	p.Thr2902Met	missense_variant	3/3		NM_001367624.2	A2
ZNF469	ENST00000437464.1	c.8621C>T	p.Thr2874Met	missense_variant	2/2	5		P4

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152246 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000988 AC: 147 AN: 148794 Hom.: 0 AF XY: 0.000925 AC XY: 74 AN XY: 80034

Gnomad AFR exome AF: 0.000278

Gnomad AMR exome AF: 0.000163

Gnomad ASJ exome AF: 0.000476

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000440

Gnomad FIN exome AF: 0.00249

Gnomad NFE exome AF: 0.00162

Gnomad OTH exome AF: 0.00211

GnomAD4 exome AF: 0.00149 AC: 2078 AN: 1395346 Hom.: 0 Cov.: 91 AF XY: 0.00142 AC XY: 978 AN XY: 688274

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.000392

Gnomad4 ASJ exome AF: 0.000675

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00193

Gnomad4 NFE exome AF: 0.00176

Gnomad4 OTH exome AF: 0.000864

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152364 Hom.: 1 Cov.: 34 AF XY: 0.00123 AC XY: 92 AN XY: 74510

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.000876

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 4

ExAC AF: 0.000501 AC: 12

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2023	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -

Ehlers-Danlos syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 27, 2022

- -

Brittle cornea syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 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	-0.64	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	11
Dann	Uncertain	0.98
DEOGEN2	Benign	0.020	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.46	T;.
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.94	N;N
Sift	Benign	0.036	D;D
Sift4G	Uncertain	0.033	D;D
Vest4		0.10
MVP		0.040
ClinPred		0.0045	T
GERP RS		-1.4
gMVP		0.13

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: rs536725615; hg19: chr16-88502583; COSMIC: COSV71258455;