16-88431120-C-T

Variant names:

• chr16-88431120-C-T
• rs115183769
• NM_001367624.2:c.3650C>T

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.3650C>T​(p.Pro1217Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,550,268 control chromosomes in the GnomAD database, including 190 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1217P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (96 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (94 hom.)
• Consequence: ZNF469 NM_001367624.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.11
• Publications: 1 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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=0.0022440255).
• BP6: Variant 16-88431120-C-T is Benign according to our data. Variant chr16-88431120-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0656 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.3650C>T	p.Pro1217Leu	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.3650C>T	p.Pro1217Leu	missense	Exon 3 of 3	ENSP00000456500.2	Q96JG9
	ZNF469	ENST00000437464.1	TSL:5	c.3566C>T	p.Pro1189Leu	missense	Exon 2 of 2	ENSP00000402343.1	A0AAA9X9E9

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2958 AN: 152110 Hom.: 96 Cov.: 33

Gnomad AFR AF: 0.0678

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00753

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: 0.000103

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00429 AC: 656 AN: 152964 AF XY: 0.00317

Gnomad AFR exome AF: 0.0702

Gnomad AMR exome AF: 0.00397

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000918

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000340

Gnomad OTH exome AF: 0.000462

GnomAD4 exome AF: 0.00203 AC: 2838 AN: 1398040 Hom.: 94 Cov.: 97 AF XY: 0.00172 AC XY: 1188 AN XY: 689518

African (AFR) AF: 0.0737 AC: 2329 AN: 31598

American (AMR) AF: 0.00389 AC: 139 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35736

South Asian (SAS) AF: 0.000265 AC: 21 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47966

Middle Eastern (MID) AF: 0.00404 AC: 23 AN: 5698

European-Non Finnish (NFE) AF: 0.0000417 AC: 45 AN: 1078940

Other (OTH) AF: 0.00481 AC: 279 AN: 57980

GnomAD4 genome AF: 0.0194 AC: 2960 AN: 152228 Hom.: 96 Cov.: 33 AF XY: 0.0184 AC XY: 1367 AN XY: 74430

African (AFR) AF: 0.0676 AC: 2808 AN: 41514

American (AMR) AF: 0.00752 AC: 115 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68012

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.0106 Hom.: 81

Bravo AF: 0.0228

ExAC AF: 0.00820 AC: 187

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

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	0.10
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.93	T
PhyloP100		1.1
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.062
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0030	D
Vest4		0.12
MVP		0.33
ClinPred		0.012	T
GERP RS		3.2
gMVP		0.035
Mutation Taster		=96/4	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: rs115183769; hg19: chr16-88497528;