16-88437002-G-T

Variant names:

• chr16-88437002-G-T
• rs887755283
• NM_001367624.2:c.9532G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001367624.2(ZNF469):​c.9532G>T​(p.Gly3178Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,369,314 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3178S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: ZNF469 NM_001367624.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.88
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.9532G>T	p.Gly3178Cys	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.9532G>T	p.Gly3178Cys	missense	Exon 3 of 3	ENSP00000456500.2	Q96JG9
	ZNF469	ENST00000437464.1	TSL:5	c.9448G>T	p.Gly3150Cys	missense	Exon 2 of 2	ENSP00000402343.1	A0AAA9X9E9

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1369314 Hom.: 0 Cov.: 91 AF XY: 0.00 AC XY: 0 AN XY: 673294

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31120

American (AMR) AF: 0.00 AC: 0 AN: 34398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24374

East Asian (EAS) AF: 0.00 AC: 0 AN: 35376

South Asian (SAS) AF: 0.00 AC: 0 AN: 77582

European-Finnish (FIN) AF: 0.0000282 AC: 1 AN: 35414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5458

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1068532

Other (OTH) AF: 0.00 AC: 0 AN: 57060

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-1.1	T
PhyloP100		7.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Vest4		0.60
MutPred		0.48		Gain of ubiquitination at K3154 (P = 0.102)
MVP		0.37
ClinPred		0.99	D
GERP RS		5.1
gMVP		0.31
Mutation Taster		=55/45	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: rs887755283; hg19: chr16-88503410;