1-63323773-C-A

Variant names:

• chr1-63323773-C-A
• rs754690288
• NM_012183.3:c.715C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012183.3(FOXD3):​c.715C>A​(p.Arg239Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FOXD3 NM_012183.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.922

Genes affected

FOXD3 (HGNC:3804): (forkhead box D3) This gene belongs to the forkhead family of transcription factors which is characterized by a distinct forkhead domain. Mutations in this gene cause autoimmune susceptibility 1. [provided by RefSeq, Nov 2008]

FOXD3-AS1 (HGNC:40241): (FOXD3 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39416215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD3	NM_012183.3	c.715C>A	p.Arg239Ser	missense_variant	Exon 1 of 1	ENST00000371116.4	NP_036315.1
FOXD3-AS1	NR_121637.1	n.87+582G>T		intron_variant	Intron 1 of 2
FOXD3-AS1	NR_121636.1	n.-98G>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXD3	ENST00000371116.4	c.715C>A	p.Arg239Ser	missense_variant	Exon 1 of 1	6	NM_012183.3	ENSP00000360157.2
FOXD3-AS1	ENST00000431294.7	n.4G>T		non_coding_transcript_exon_variant	Exon 1 of 3	1
FOXD3-AS1	ENST00000427268.1	n.87+582G>T		intron_variant	Intron 1 of 2	1
FOXD3-AS1	ENST00000697579.1	n.-98G>T		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249738 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135486

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461402 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727018

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.715C>A (p.R239S) alteration is located in exon 1 (coding exon 1) of the FOXD3 gene. This alteration results from a C to A substitution at nucleotide position 715, causing the arginine (R) at amino acid position 239 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	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Benign	1.1	L
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.77	P
Vest4		0.32
MutPred		0.48		Gain of phosphorylation at R239 (P = 0.0189);
MVP		0.43
ClinPred		0.85	D
GERP RS		2.4
Varity_R		0.84
gMVP		0.96

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: rs754690288; hg19: chr1-63789444; COSMIC: COSV99058286; COSMIC: COSV99058286;