rs755348435

Variant names:

• chr16-88430922-C-T
• rs755348435
• NM_001367624.2:c.3452C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-88430922-C-T
• chr16-88430922-C-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.3452C>T​(p.Ala1151Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000286 in 1,535,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A1151A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ZNF469 NM_001367624.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: -3.65
• 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=0.060614407).

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.3452C>T	p.Ala1151Val	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.3452C>T	p.Ala1151Val	missense	Exon 3 of 3	ENSP00000456500.2	Q96JG9
	ZNF469	ENST00000437464.1	TSL:5	c.3368C>T	p.Ala1123Val	missense	Exon 2 of 2	ENSP00000402343.1	A0AAA9X9E9

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152022 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000893 AC: 12 AN: 134370 AF XY: 0.0000951

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000334

Gnomad ASJ exome AF: 0.000248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000386

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 34 AN: 1383796 Hom.: 0 Cov.: 75 AF XY: 0.0000220 AC XY: 15 AN XY: 682678

African (AFR) AF: 0.00 AC: 0 AN: 31354

American (AMR) AF: 0.000369 AC: 13 AN: 35238

Ashkenazi Jewish (ASJ) AF: 0.000160 AC: 4 AN: 25050

East Asian (EAS) AF: 0.00 AC: 0 AN: 35656

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 79024

European-Finnish (FIN) AF: 0.0000533 AC: 2 AN: 37544

Middle Eastern (MID) AF: 0.000202 AC: 1 AN: 4942

European-Non Finnish (NFE) AF: 0.00000464 AC: 5 AN: 1077356

Other (OTH) AF: 0.000139 AC: 8 AN: 57632

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152022 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74248

African (AFR) AF: 0.0000241 AC: 1 AN: 41408

American (AMR) AF: 0.000327 AC: 5 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

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

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67966

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.0000497 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.054
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.42	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.99	T
PhyloP100		-3.7
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.12
Sift	Benign	0.095	T
Sift4G	Uncertain	0.015	D
Vest4		0.034
MutPred		0.22		Gain of loop (P = 0.0097)
MVP		0.10
ClinPred		0.081	T
GERP RS		-7.3
gMVP		0.032
Mutation Taster		=91/9	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: rs755348435; hg19: chr16-88497330;