16-88430136-C-T

Position:

• chr16-88430136-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.2666C>T​(p.Ala889Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,550,136 control chromosomes in the GnomAD database, including 46 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 0.010 (23 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: ZNF469 NM_001367624.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0840

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]

LOC112268182 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016812086).
• BP6: Variant 16-88430136-C-T is Benign according to our data. Variant chr16-88430136-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 320889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88430136-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.01 (1530/152260) while in subpopulation AFR AF= 0.0341 (1417/41530). AF 95% confidence interval is 0.0326. There are 23 homozygotes in gnomad4. There are 717 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF469	NM_001367624.2	c.2666C>T	p.Ala889Val	missense_variant	3/3	ENST00000565624.3	NP_001354553.1
ZNF469	XM_047434810.1	c.2666C>T	p.Ala889Val	missense_variant	4/4		XP_047290766.1
LOC112268182	XR_007065178.1	n.92-14G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF469	ENST00000565624.3	c.2666C>T	p.Ala889Val	missense_variant	3/3	6	NM_001367624.2	ENSP00000456500.2
ZNF469	ENST00000437464.1	c.2666C>T	p.Ala889Val	missense_variant	1/2	5		ENSP00000402343.1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1526 AN: 152142 Hom.: 24 Cov.: 34

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

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: 0.000147

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00225 AC: 334 AN: 148484 Hom.: 4 AF XY: 0.00174 AC XY: 139 AN XY: 79942

Gnomad AFR exome AF: 0.0334

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000442

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000269

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00112 AC: 1572 AN: 1397876 Hom.: 23 Cov.: 65 AF XY: 0.00103 AC XY: 711 AN XY: 689438

Gnomad4 AFR exome AF: 0.0364

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000101

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000936

Gnomad4 OTH exome AF: 0.00307

GnomAD4 genome AF: 0.0100 AC: 1530 AN: 152260 Hom.: 23 Cov.: 34 AF XY: 0.00963 AC XY: 717 AN XY: 74476

Gnomad4 AFR AF: 0.0341

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00141 Hom.: 3

Bravo AF: 0.0111

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00237 AC: 52

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 30, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Brittle cornea syndrome 1 Benign:2

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

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 13, 2022

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2019

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	0.10
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.46
DANN	Benign	0.83
DEOGEN2	Benign	0.0017	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.48	T;.
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-0.93	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.69	N;N
REVEL	Benign	0.036
Sift	Benign	1.0	T;T
Sift4G	Benign	0.51	T;T
Vest4		0.019
MVP		0.12
ClinPred		0.0016	T
GERP RS		-4.2
gMVP		0.054

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs145186655; hg19: chr16-88496544;