dbSNP rs751970827: FOXC1:p.Asp178Asn (chr6-1610977-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001453.3(FOXC1):c.532G>A(p.Asp178Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,274 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

FOXC1
NM_001453.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.75

Variant links:

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]

FOXC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXC1	NM_001453.3 link	c.532G>A	p.Asp178Asn	missense_variant	Exon 1 of 1	ENST00000645831.2	NP_001444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXC1	ENST00000645831.2 link	c.532G>A	p.Asp178Asn	missense_variant	Exon 1 of 1		NM_001453.3	ENSP00000493906.1		Q12948

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461274

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726948

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.532G>A (p.D178N) alteration is located in exon 1 (coding exon 1) of the FOXC1 gene. This alteration results from a G to A substitution at nucleotide position 532, causing the aspartic acid (D) at amino acid position 178 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;D

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

.;D

M_CAP

Pathogenic

0.69

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

1.8

L;L

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-4.5

D;.

REVEL

Uncertain

0.60

Sift

Uncertain

0.016

D;.

Sift4G

Uncertain

0.010

D;.

Polyphen

0.99

D;D

Vest4

0.29

MutPred

0.22

Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);

MVP

0.95

ClinPred

0.99

GERP RS

3.7

Varity_R

0.53

gMVP

0.76

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over