chr1-63323593-A-G

Variant names:

• chr1-63323593-A-G
• rs28553389
• NM_012183.3:c.535A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_012183.3(FOXD3):​c.535A>G​(p.Arg179Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FOXD3 NM_012183.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD3	NM_012183.3	c.535A>G	p.Arg179Gly	missense_variant	Exon 1 of 1	ENST00000371116.4	NP_036315.1
FOXD3-AS1	NR_121636.1	n.83T>C		non_coding_transcript_exon_variant	Exon 1 of 3
FOXD3-AS1	NR_121637.1	n.87+762T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXD3	ENST00000371116.4	c.535A>G	p.Arg179Gly	missense_variant	Exon 1 of 1	6	NM_012183.3	ENSP00000360157.2
FOXD3-AS1	ENST00000431294.7	n.184T>C		non_coding_transcript_exon_variant	Exon 1 of 3	1
FOXD3-AS1	ENST00000427268.1	n.87+762T>C		intron_variant	Intron 1 of 2	1
FOXD3-AS1	ENST00000697579.1	n.83T>C		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.535A>G (p.R179G) alteration is located in exon 1 (coding exon 1) of the FOXD3 gene. This alteration results from a A to G substitution at nucleotide position 535, causing the arginine (R) at amino acid position 179 to be replaced by a glycine (G). 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	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Benign	-0.018
Eigen_PC	Benign	-0.074
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.39	B
Vest4		0.75
MutPred		0.77		Gain of ubiquitination at K181 (P = 0.053);
MVP		0.84
ClinPred		0.99	D
GERP RS		2.0
Varity_R		0.80
gMVP		0.99

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: rs28553389; hg19: chr1-63789264;