Genetic Variant FOXD2:p.Gly100Ser (chr1-47438433-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004474.4(FOXD2):c.298G>A(p.Gly100Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000109 in 914,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000011 ( 0 hom. )

Consequence

FOXD2
NM_004474.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.08

Publications

0 publications found

Variant links:

Genes affected

FOXD2 (HGNC:3803): (forkhead box D2) This gene belongs to the forkhead family of transcription factors which is characterized by a distinct forkhead domain. The specific function of this gene has not yet been determined. [provided by RefSeq, Jul 2008]

FOXD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21704355).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD2	NM_004474.4 link	c.298G>A	p.Gly100Ser	missense_variant	Exon 1 of 1	ENST00000334793.6	NP_004465.3	O60548

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXD2	ENST00000334793.6 link	c.298G>A	p.Gly100Ser	missense_variant	Exon 1 of 1	6	NM_004474.4	ENSP00000335493.6		O60548

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000109

AC:

AN:

914124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

427772

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17678

American (AMR)

AF:

0.00

AC:

AN:

3300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7450

East Asian (EAS)

AF:

0.00

AC:

AN:

10098

South Asian (SAS)

AF:

0.00

AC:

AN:

18022

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12228

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2030

European-Non Finnish (NFE)

AF:

0.00000123

AC:

AN:

811124

Other (OTH)

AF:

0.00

AC:

AN:

32194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 12, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.298G>A (p.G100S) alteration is located in exon 1 (coding exon 1) of the FOXD2 gene. This alteration results from a G to A substitution at nucleotide position 298, causing the glycine (G) at amino acid position 100 to be replaced by a serine (S). 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

Benign

0.13

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.054

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.44

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.0

PhyloP100

3.1

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.39

REVEL

Benign

0.21

Sift

Benign

0.88

Sift4G

Benign

0.49

Polyphen

0.15

Vest4

0.11

MutPred

0.36

Gain of glycosylation at G100 (P = 0.0035);

MVP

0.77

ClinPred

0.16

GERP RS

3.4

PromoterAI

-0.020

Neutral

(source)

Varity_R

0.11

gMVP

0.21

Mutation Taster

=89/11

polymorphism

(source)

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

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1-47438433-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over