rs35717904

Positions:

• chr6-1612841-A-T

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.*734A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 212,012 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (1 hom.)
• Consequence: FOXC1 NM_001453.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 B:1
• Conservation: PhyloP100: 2.48

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 (BayesDel_noAF=-0.46).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00351 (534/152332) while in subpopulation NFE AF= 0.00513 (349/68040). AF 95% confidence interval is 0.00469. There are 3 homozygotes in gnomad4. There are 253 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 534 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXC1	NM_001453.3	c.*734A>T		3_prime_UTR_variant	1/1	ENST00000645831.2	NP_001444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXC1	ENST00000645831.2	c.*734A>T		3_prime_UTR_variant	1/1		NM_001453.3	ENSP00000493906	P1

Frequencies

GnomAD3 genomes AF: 0.00351 AC: 534 AN: 152214 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00513

Gnomad OTH AF: 0.00384

GnomAD4 exome AF: 0.00365 AC: 218 AN: 59680 Hom.: 1 Cov.: 0 AF XY: 0.00342 AC XY: 95 AN XY: 27806

Gnomad4 AFR exome AF: 0.000536

Gnomad4 AMR exome AF: 0.00496

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00538

Gnomad4 OTH exome AF: 0.00560

GnomAD4 genome AF: 0.00351 AC: 534 AN: 152332 Hom.: 3 Cov.: 33 AF XY: 0.00340 AC XY: 253 AN XY: 74504

Gnomad4 AFR AF: 0.000987

Gnomad4 AMR AF: 0.00490

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00513

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00355 Hom.: 0

Bravo AF: 0.00387

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

not provided

Human Genetics School of Medicine of Albacete, Castilla-La Mancha University

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

FOXC1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	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: rs35717904; hg19: chr6-1613076;