chr16-88432736-G-A

Variant names:

• chr16-88432736-G-A
• rs371328036
• NM_001367624.2:c.5266G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001367624.2(ZNF469):​c.5266G>A​(p.Ala1756Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,550,392 control chromosomes in the GnomAD database, with no homozygous occurrence. 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).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: ZNF469 NM_001367624.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: -3.20
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013830751).

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.5266G>A	p.Ala1756Thr	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.5266G>A	p.Ala1756Thr	missense	Exon 3 of 3	ENSP00000456500.2	Q96JG9
	ZNF469	ENST00000437464.1	TSL:5	c.5182G>A	p.Ala1728Thr	missense	Exon 2 of 2	ENSP00000402343.1	A0AAA9X9E9

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000177 AC: 27 AN: 152610 AF XY: 0.000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000324

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000656

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000223 AC: 312 AN: 1398070 Hom.: 0 Cov.: 95 AF XY: 0.000207 AC XY: 143 AN XY: 689520

African (AFR) AF: 0.0000316 AC: 1 AN: 31598

American (AMR) AF: 0.000364 AC: 13 AN: 35704

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

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

South Asian (SAS) AF: 0.000202 AC: 16 AN: 79236

European-Finnish (FIN) AF: 0.000125 AC: 6 AN: 47982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.000248 AC: 268 AN: 1078960

Other (OTH) AF: 0.000138 AC: 8 AN: 57980

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74476

African (AFR) AF: 0.0000722 AC: 3 AN: 41570

American (AMR) AF: 0.000196 AC: 3 AN: 15308

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000264 Hom.: 0

Bravo AF: 0.000136

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.000178 AC: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	2	-	not specified (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0040
DANN	Benign	0.68
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0065	N
LIST_S2	Benign	0.37	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.94	T
PhyloP100		-3.2
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.042
Sift	Benign	1.0	T
Sift4G	Uncertain	0.054	T
Vest4		0.038
MVP		0.13
ClinPred		0.022	T
GERP RS		-4.9
gMVP		0.012
Mutation Taster		=89/11	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: rs371328036; hg19: chr16-88499144;