Genetic Variant FOXD3:p.Asp45Asn (chr1-63323191-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_012183.3(FOXD3):c.133G>A(p.Asp45Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. D45H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FOXD3
NM_012183.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.53

Publications

0 publications found

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:

ENSG00000293613 (HGNC:):

ENSG00000293613 links:

ITGB3BP (HGNC:6157): (integrin subunit beta 3 binding protein) This gene encodes a transcriptional coregulator that binds to and enhances the activity of members of the nuclear receptor families, thyroid hormone receptors and retinoid X receptors. This protein also acts as a corepressor of NF-kappaB-dependent signaling. This protein induces apoptosis in breast cancer cells through a caspase 2-mediated signaling pathway. This protein is also a component of the centromere-specific histone H3 variant nucleosome associated complex (CENP-NAC) and may be involved in mitotic progression by recruiting the histone H3 variant CENP-A to the centromere. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

ITGB3BP links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34119955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD3	NM_012183.3 link	c.133G>A	p.Asp45Asn	missense_variant	Exon 1 of 1	ENST00000371116.4	NP_036315.1	Q9UJU5
FOXD3-AS1	NR_121636.1 link	n.185+300C>T		intron_variant	Intron 1 of 2
FOXD3-AS1	NR_121637.1 link	n.87+1164C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXD3	ENST00000371116.4 link	c.133G>A	p.Asp45Asn	missense_variant	Exon 1 of 1	6	NM_012183.3	ENSP00000360157.2		Q9UJU5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1399222

Hom.:

Cov.:

AF XY:

0.00000289

AC XY:

AN XY:

691728

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29968

American (AMR)

AF:

0.00

AC:

AN:

36764

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24740

East Asian (EAS)

AF:

0.00

AC:

AN:

34562

South Asian (SAS)

AF:

0.00

AC:

AN:

79628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47114

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

9.24e-7

AC:

AN:

1082810

Other (OTH)

AF:

0.00

AC:

AN:

58028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Benign

-0.069

Eigen_PC

Benign

-0.050

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.57

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.34

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

0.34

PhyloP100

3.5

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.83

REVEL

Benign

0.28

Sift

Benign

0.13

Sift4G

Benign

0.52

Polyphen

0.92

Vest4

0.067

MutPred

0.15

Gain of catalytic residue at D45 (P = 0.1095);

MVP

0.76

ClinPred

0.68

GERP RS

2.7

Varity_R

0.11

gMVP

0.33

Mutation Taster

=91/9

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over