rs77490207

Variant names:

• chr16-88434414-C-G
• rs77490207
• NM_001367624.2:c.6944C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001367624.2(ZNF469):​c.6944C>G​(p.Pro2315Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,549,764 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (70 hom., cov: 34)
  • Exomes 𝑓: 0.0016 (66 hom.)
• Consequence: ZNF469 NM_001367624.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.314
• Publications: 5 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026768148).
• BP6: Variant 16-88434414-C-G is Benign according to our data. Variant chr16-88434414-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 320962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF469	NM_001367624.2	MANE Select	c.6944C>G	p.Pro2315Arg	missense	Exon 3 of 3	NP_001354553.1	Q96JG9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF469	ENST00000565624.3	TSL:6 MANE Select	c.6944C>G	p.Pro2315Arg	missense	Exon 3 of 3	ENSP00000456500.2	Q96JG9
	ZNF469	ENST00000437464.1	TSL:5	c.6860C>G	p.Pro2287Arg	missense	Exon 2 of 2	ENSP00000402343.1	A0AAA9X9E9

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2510 AN: 152200 Hom.: 69 Cov.: 34

Gnomad AFR AF: 0.0573

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

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: 0.000220

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00378 AC: 567 AN: 149838 AF XY: 0.00288

Gnomad AFR exome AF: 0.0620

Gnomad AMR exome AF: 0.00422

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000175

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.00164 AC: 2291 AN: 1397446 Hom.: 66 Cov.: 98 AF XY: 0.00141 AC XY: 973 AN XY: 689270

African (AFR) AF: 0.0574 AC: 1815 AN: 31596

American (AMR) AF: 0.00454 AC: 162 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25174

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.0000505 AC: 4 AN: 79226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47404

Middle Eastern (MID) AF: 0.00211 AC: 12 AN: 5698

European-Non Finnish (NFE) AF: 0.0000436 AC: 47 AN: 1078932

Other (OTH) AF: 0.00431 AC: 250 AN: 57980

GnomAD4 genome AF: 0.0165 AC: 2518 AN: 152318 Hom.: 70 Cov.: 34 AF XY: 0.0161 AC XY: 1198 AN XY: 74486

African (AFR) AF: 0.0573 AC: 2382 AN: 41550

American (AMR) AF: 0.00627 AC: 96 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68026

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00512 Hom.: 3

Bravo AF: 0.0191

ExAC AF: 0.00461 AC: 116

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Brittle cornea syndrome 1 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.55
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.31
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.041
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.028	D
Vest4		0.18
MVP		0.44
ClinPred		0.0053	T
GERP RS		2.4
gMVP		0.061
Mutation Taster		=88/12	polymorphism (auto)

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: rs77490207; hg19: chr16-88500822; COSMIC: COSV99081570;