rs200668806

Variant names:

• chr16-88438358-C-T
• rs200668806
• NM_001367624.2:c.10888C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3630H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (12 hom.)
• Consequence: ZNF469 NM_001367624.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 1.06
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• brittle cornea syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
• brittle cornea syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• aortic disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 421677.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367624.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF469	NM_001367624.2	MANE Select	c.10888C>T	p.Arg3630Cys	missense	Exon 3 of 3	NP_001354553.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF469	ENST00000565624.3	TSL:6 MANE Select	c.10888C>T	p.Arg3630Cys	missense	Exon 3 of 3	ENSP00000456500.2
	ZNF469	ENST00000437464.1	TSL:5	c.10804C>T	p.Arg3602Cys	missense	Exon 2 of 2	ENSP00000402343.1

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 273 AN: 152168 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.00152 AC: 226 AN: 149024 AF XY: 0.00141

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 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.: 12 Cov.: 92 AF XY: 0.00310 AC XY: 2139 AN XY: 689446

African (AFR) AF: 0.000665 AC: 21 AN: 31598

American (AMR) AF: 0.000756 AC: 27 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.0000505 AC: 4 AN: 79234

European-Finnish (FIN) AF: 0.000230 AC: 11 AN: 47834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00390 AC: 4203 AN: 1078940

Other (OTH) AF: 0.00398 AC: 231 AN: 57984

GnomAD4 genome AF: 0.00179 AC: 273 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.00187 AC XY: 139 AN XY: 74454

African (AFR) AF: 0.000577 AC: 24 AN: 41562

American (AMR) AF: 0.00111 AC: 17 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00329 AC: 224 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00235 Hom.: 2

Bravo AF: 0.00193

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ExAC AF: 0.00111 AC: 24

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	2	-	Brittle cornea syndrome 1 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Benign	0.30
DEOGEN2	Benign	0.0054	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.99	T
PhyloP100		1.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.057
Sift	Benign	0.098	T
Sift4G	Benign	0.10	T
Vest4		0.14
MVP		0.27
ClinPred		0.018	T
GERP RS		2.2
gMVP		0.022
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs200668806; hg19: chr16-88504766; COSMIC: COSV104714912;