rs104893954

chr6-1610706-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001453.3(FOXC1):c.261C>G(p.Ile87Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. I87I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FOXC1 NM_001453.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.42

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001453.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 6-1610706-C-G is Pathogenic according to our data. Variant chr6-1610706-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 8459.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXC1	NM_001453.3	c.261C>G	p.Ile87Met	missense_variant	1/1	ENST00000645831.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXC1	ENST00000645831.2	c.261C>G	p.Ile87Met	missense_variant	1/1		NM_001453.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Anterior segment dysgenesis 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.8	D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.95		Gain of phosphorylation at Y83 (P = 0.0823);Gain of phosphorylation at Y83 (P = 0.0823);
MVP		0.99
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.93
gMVP		0.87

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: rs104893954; hg19: chr6-1610941;