6-1610202-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001453.3(FOXC1):c.-244C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 152,226 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (33 hom., cov: 31)
  • Exomes 𝑓: 0.0059 (0 hom.)
• Consequence: FOXC1 NM_001453.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter P:1 B:2
• Conservation: PhyloP100: -0.740

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-1610202-C-T is Benign according to our data. Variant chr6-1610202-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 183250.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.013 (1976/151720) while in subpopulation NFE AF= 0.0208 (1409/67820). AF 95% confidence interval is 0.0199. There are 33 homozygotes in gnomad4. There are 981 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 1978 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXC1	NM_001453.3	c.-244C>T		5_prime_UTR_variant	1/1	ENST00000645831.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXC1	ENST00000645831.2	c.-244C>T		5_prime_UTR_variant	1/1		NM_001453.3	P1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1978 AN: 151612 Hom.: 33 Cov.: 31

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00715

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0310

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0208

Gnomad OTH AF: 0.00337

GnomAD4 exome AF: 0.00593 AC: 3 AN: 506 Hom.: 0 Cov.: 0 AF XY: 0.00806 AC XY: 2 AN XY: 248

Gnomad4 AFR 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: 0.00620

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0130 AC: 1976 AN: 151720 Hom.: 33 Cov.: 31 AF XY: 0.0132 AC XY: 981 AN XY: 74168

Gnomad4 AFR AF: 0.00193

Gnomad4 AMR AF: 0.00714

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.0310

Gnomad4 NFE AF: 0.0208

Gnomad4 OTH AF: 0.00333

Alfa AF: 0.0238 Hom.: 21

Bravo AF: 0.00931

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	not provided	Human Genetics School of Medicine of Albacete, Castilla-La Mancha University	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2021	See Variant Classification Assertion Criteria. -

Anterior segment dysgenesis 3 Benign:1

Benign, no assertion criteria provided

curation

Reproductive Health Research and Development, BGI Genomics

Jan 06, 2020

NG_009368.1(NM_001453.2):c.-244C>T in FOXC1 gene has an allele frequency of 0.041 in European (non-Finnish) subpopulation in the gnomAD database, including 27 homozygous occurrences. Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1, BS2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	6.1
Dann	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs185790394; hg19: chr6-1610437;