Genetic Variant FOXD3:p.Pro73Gln (chr1-63323276-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012183.3(FOXD3):c.218C>A(p.Pro73Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000298 in 1,341,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. P73R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000030 ( 0 hom. )

Consequence

FOXD3
NM_012183.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.32

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17953771).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD3	NM_012183.3 link	c.218C>A	p.Pro73Gln	missense_variant	Exon 1 of 1	ENST00000371116.4	NP_036315.1	Q9UJU5
FOXD3-AS1	NR_121636.1 link	n.185+215G>T		intron_variant	Intron 1 of 2
FOXD3-AS1	NR_121637.1 link	n.87+1079G>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.218C>A	p.Pro73Gln	missense_variant	Exon 1 of 1	6	NM_012183.3	ENSP00000360157.2		Q9UJU5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000298

AC:

AN:

1341468

Hom.:

Cov.:

AF XY:

0.00000303

AC XY:

AN XY:

660206

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26320

American (AMR)

AF:

0.0000364

AC:

AN:

27474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23086

East Asian (EAS)

AF:

0.00

AC:

AN:

29728

South Asian (SAS)

AF:

0.00

AC:

AN:

74390

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44760

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4520

European-Non Finnish (NFE)

AF:

0.00000189

AC:

AN:

1055788

Other (OTH)

AF:

0.0000180

AC:

AN:

55402

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.40

M_CAP

Pathogenic

0.82

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.55

PhyloP100

1.3

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.090

REVEL

Benign

0.16

Sift

Benign

0.25

Sift4G

Benign

0.28

Polyphen

0.065

Vest4

0.13

MutPred

0.27

Loss of catalytic residue at P73 (P = 0.0064);

MVP

0.17

ClinPred

0.55

GERP RS

1.7

Varity_R

0.077

gMVP

0.23

Mutation Taster

=80/20

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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chr1-63323276-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over