Genetic Variant FOXD3:p.Ala268Ala (chr1-63323862-G-A) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP7BS2

The NM_012183.3(FOXD3):c.804G>A(p.Ala268Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000054 in 1,555,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A268A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000093 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

FOXD3
NM_012183.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.72

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP7

Synonymous conserved (PhyloP=1.72 with no splicing effect.

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD3	NM_012183.3 link	c.804G>A	p.Ala268Ala	synonymous_variant	Exon 1 of 1	ENST00000371116.4	NP_036315.1	Q9UJU5
FOXD3-AS1	NR_121637.1 link	n.87+493C>T		intron_variant	Intron 1 of 2
FOXD3-AS1	NR_121636.1 link	n.-187C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXD3	ENST00000371116.4 link	c.804G>A	p.Ala268Ala	synonymous_variant	Exon 1 of 1	6	NM_012183.3	ENSP00000360157.2		Q9UJU5

Frequencies

GnomAD3 genomes

AF:

0.0000927

AC:

AN:

150994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

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:

0.0000739

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000307

AC:

AN:

163088

AF XY:

0.0000220

show subpopulations

Gnomad AFR exome

AF:

0.000114

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000575

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000498

AC:

AN:

1404924

Hom.:

Cov.:

AF XY:

0.0000445

AC XY:

AN XY:

696394

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

31036

American (AMR)

AF:

0.00

AC:

AN:

31654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24474

East Asian (EAS)

AF:

0.00

AC:

AN:

37660

South Asian (SAS)

AF:

0.00

AC:

AN:

80830

European-Finnish (FIN)

AF:

0.0000209

AC:

AN:

47916

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4048

European-Non Finnish (NFE)

AF:

0.0000560

AC:

AN:

1089422

Other (OTH)

AF:

0.0000346

AC:

AN:

57884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000927

AC:

AN:

150994

Hom.:

Cov.:

AF XY:

0.0000407

AC XY:

AN XY:

73700

show subpopulations

African (AFR)

AF:

0.000194

AC:

AN:

41244

American (AMR)

AF:

0.0000658

AC:

AN:

15190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3430

East Asian (EAS)

AF:

0.00

AC:

AN:

5064

South Asian (SAS)

AF:

0.00

AC:

AN:

4788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000739

AC:

AN:

67630

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000945

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

1.7

Mutation Taster

=100/0

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over