6-1611252-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001453.3(FOXC1):c.807C>G(p.Ser269Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,429,706 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S269S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: FOXC1 NM_001453.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.783

Genes affected

FOXC1 (HGNC:3800): (forkhead box C1) This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. The specific function of this gene has not yet been determined; however, it has been shown to play a role in the regulation of embryonic and ocular development. Mutations in this gene cause various glaucoma phenotypes including primary congenital glaucoma, autosomal dominant iridogoniodysgenesis anomaly, and Axenfeld-Rieger anomaly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20627597).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000174 (26/149730) while in subpopulation AMR AF= 0.00166 (25/15076). AF 95% confidence interval is 0.00115. There are 1 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXC1	NM_001453.3	c.807C>G	p.Ser269Arg	missense_variant	1/1	ENST00000645831.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXC1	ENST00000645831.2	c.807C>G	p.Ser269Arg	missense_variant	1/1		NM_001453.3	P1

Frequencies

GnomAD3 genomes AF: 0.000174 AC: 26 AN: 149730 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00166

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000386 AC: 3 AN: 77786 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 44774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000201

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000133 AC: 17 AN: 1279976 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 7 AN XY: 631584

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000237

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000391

Gnomad4 OTH exome AF: 0.000135

GnomAD4 genome AF: 0.000174 AC: 26 AN: 149730 Hom.: 1 Cov.: 32 AF XY: 0.000192 AC XY: 14 AN XY: 73060

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00166

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000149

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000166

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Axenfeld-Rieger syndrome type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2023

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 269 of the FOXC1 protein (p.Ser269Arg). This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FOXC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 469654). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	19
Dann	Benign	0.93
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.49	N
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.99	N;.
REVEL	Uncertain	0.32
Sift	Benign	0.37	T;.
Sift4G	Benign	0.092	T;.
Polyphen		0.50	P;P
Vest4		0.19
MutPred		0.34		Loss of phosphorylation at S269 (P = 8e-04);Loss of phosphorylation at S269 (P = 8e-04);
MVP		0.91
ClinPred		0.095	T
GERP RS		1.3
Varity_R		0.099
gMVP		0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs1277775861; hg19: chr6-1611487;