chr1-63323453-C-A

Position:

• chr1-63323453-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012183.3(FOXD3):​c.395C>A​(p.Pro132Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,453,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: 0.0000028 (0 hom.)
• Consequence: FOXD3 NM_012183.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.702

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16014162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXD3	NM_012183.3	c.395C>A	p.Pro132Gln	missense_variant	1/1	ENST00000371116.4
FOXD3-AS1	NR_121637.1	n.87+902G>T		intron_variant, non_coding_transcript_variant
FOXD3-AS1	NR_121636.1	n.185+38G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXD3	ENST00000371116.4	c.395C>A	p.Pro132Gln	missense_variant	1/1		NM_012183.3	P1
FOXD3-AS1	ENST00000427268.1	n.87+902G>T		intron_variant, non_coding_transcript_variant		1
FOXD3-AS1	ENST00000431294.7	n.286+38G>T		intron_variant, non_coding_transcript_variant		1
FOXD3-AS1	ENST00000697579.1	n.203+20G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1453260 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 723042

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: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.395C>A (p.P132Q) 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 395, causing the proline (P) at amino acid position 132 to be replaced by a glutamine (Q). 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	0.11
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.89	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.21	N
REVEL	Benign	0.14
Sift	Benign	0.24	T
Sift4G	Benign	0.72	T
Polyphen		0.080	B
Vest4		0.12
MutPred		0.22		Loss of glycosylation at P132 (P = 0.0191);
MVP		0.55
ClinPred		0.20	T
GERP RS		2.6
Varity_R		0.098
gMVP		0.46

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: rs747009146; hg19: chr1-63789124;