6-1611334-C-T

Position:

• chr6-1611334-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001453.3(FOXC1):​c.889C>T​(p.Pro297Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0058 in 1,419,488 control chromosomes in the GnomAD database, including 351 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (182 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (169 hom.)
• Consequence: FOXC1 NM_001453.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:2 B:4
• Conservation: PhyloP100: 1.69

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017443299).
• BP6: Variant 6-1611334-C-T is Benign according to our data. Variant chr6-1611334-C-T is described in ClinVar as [Benign]. Clinvar id is 30156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-1611334-C-T is described in Lovd as [Likely_pathogenic].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0941 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXC1	NM_001453.3	c.889C>T	p.Pro297Ser	missense_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.889C>T	p.Pro297Ser	missense_variant	1/1		NM_001453.3	ENSP00000493906	P1

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4293 AN: 150208 Hom.: 179 Cov.: 32

Gnomad AFR AF: 0.0966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.000582

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000847

Gnomad OTH AF: 0.0257

GnomAD3 exomes AF: 0.00284 AC: 213 AN: 75104 Hom.: 12 AF XY: 0.00217 AC XY: 94 AN XY: 43388

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.00515

Gnomad ASJ exome AF: 0.000460

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000183

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000691

Gnomad OTH exome AF: 0.00461

GnomAD4 exome AF: 0.00310 AC: 3930 AN: 1269172 Hom.: 169 Cov.: 32 AF XY: 0.00269 AC XY: 1685 AN XY: 625620

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.00611

Gnomad4 ASJ exome AF: 0.000329

Gnomad4 EAS exome AF: 0.0000389

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000532

Gnomad4 OTH exome AF: 0.00700

GnomAD4 genome AF: 0.0286 AC: 4301 AN: 150316 Hom.: 182 Cov.: 32 AF XY: 0.0271 AC XY: 1986 AN XY: 73418

Gnomad4 AFR AF: 0.0966

Gnomad4 AMR AF: 0.0126

Gnomad4 ASJ AF: 0.000582

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000847

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0209 Hom.: 12

Bravo AF: 0.0320

ExAC AF: 0.00247 AC: 189

ClinVar

Significance: Benign

Submissions summary: Pathogenic:2 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27884173, 17197537, 25093829, 21423868, 19626132, 19793056) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Mar 23, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2016	- -

Anterior segment dysgenesis 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2009

- -

Axenfeld-Rieger syndrome type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.37	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.34	.;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.7	N;.
REVEL	Benign	0.19
Sift	Benign	0.17	T;.
Sift4G	Benign	0.65	T;.
Polyphen		0.26	B;B
Vest4		0.14
MVP		0.81
ClinPred		0.0048	T
GERP RS		-0.40
Varity_R		0.044
gMVP		0.32

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: rs79691946; hg19: chr6-1611569;