Genetic Variant FOXD3:p.Gly276Ser (chr1-63323884-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012183.3(FOXD3):c.826G>A(p.Gly276Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000776 in 1,289,274 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G276R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.8e-7 ( 0 hom. )

Consequence

FOXD3
NM_012183.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.97

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012183.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXD3	NM_012183.3	MANE Select	c.826G>A	p.Gly276Ser	missense	Exon 1 of 1	NP_036315.1	Q9UJU5
FOXD3-AS1	NR_121637.1		n.87+471C>T		intron	N/A
FOXD3-AS1	NR_121636.1		n.-209C>T		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXD3	ENST00000371116.4	TSL:6 MANE Select	c.826G>A	p.Gly276Ser	missense	Exon 1 of 1	ENSP00000360157.2	Q9UJU5
FOXD3-AS1	ENST00000427268.2	TSL:1	n.196+471C>T		intron	N/A
ENSG00000293613	ENST00000715889.1		n.38+825C>T		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.76e-7

AC:

AN:

1289274

Hom.:

Cov.:

AF XY:

0.00000158

AC XY:

AN XY:

633564

show subpopulations

African (AFR)

AF:

0.0000400

AC:

AN:

24984

American (AMR)

AF:

0.00

AC:

AN:

14032

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19482

East Asian (EAS)

AF:

0.00

AC:

AN:

29768

South Asian (SAS)

AF:

0.00

AC:

AN:

62764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3608

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1038514

Other (OTH)

AF:

0.00

AC:

AN:

52776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

Eigen

Benign

0.14

Eigen_PC

Benign

0.065

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.49

MetaRNN

Uncertain

0.54

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

0.97

PhyloP100

4.0

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.46

Sift

Benign

0.051

Sift4G

Uncertain

0.016

Polyphen

1.0

Vest4

0.27

MutPred

0.31

Gain of glycosylation at G276 (P = 0.0011)

MVP

0.79

ClinPred

0.90

GERP RS

2.4

Varity_R

0.34

gMVP

0.78

Mutation Taster

=27/73

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over