Genetic Variant FOXD3:p.Pro50Gln (chr1-63323207-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_012183.3(FOXD3):c.149C>A(p.Pro50Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000306 in 1,538,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P50L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

FOXD3
NM_012183.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.313

Variant links:

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 links:

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

FOXD3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23195368).

BS2

High AC in GnomAdExome4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD3	NM_012183.3 link	c.149C>A	p.Pro50Gln	missense_variant	Exon 1 of 1	ENST00000371116.4	NP_036315.1	Q9UJU5
FOXD3-AS1	NR_121636.1 link	n.185+284G>T		intron_variant	Intron 1 of 2
FOXD3-AS1	NR_121637.1 link	n.87+1148G>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXD3	ENST00000371116.4 link	c.149C>A	p.Pro50Gln	missense_variant	Exon 1 of 1	6	NM_012183.3	ENSP00000360157.2	Q9UJU5
FOXD3-AS1	ENST00000427268.1 link	n.87+1148G>T		intron_variant	Intron 1 of 2	1
FOXD3-AS1	ENST00000431294.7 link	n.286+284G>T		intron_variant	Intron 1 of 2	1
FOXD3-AS1	ENST00000697579.1 link	n.203+266G>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000226

AC:

AN:

132924

Hom.:

AF XY:

0.0000414

AC XY:

AN XY:

72386

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000422

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000404

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000325

AC:

AN:

1386246

Hom.:

Cov.:

AF XY:

0.0000336

AC XY:

AN XY:

684420

show subpopulations

Gnomad4 AFR exome

AF:

0.0000343

Gnomad4 AMR exome

AF:

0.0000282

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:

0.0000390

Gnomad4 OTH exome

AF:

0.0000174

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.84

REVEL

Benign

0.24

Sift

Benign

0.30

Sift4G

Benign

0.59

Polyphen

0.83

Vest4

0.15

MutPred

0.27

Loss of helix (P = 0.079);

MVP

0.67

ClinPred

0.14

GERP RS

2.7

Varity_R

0.14

gMVP

0.20

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over