chr1-63323884-G-A

Variant names:

• chr1-63323884-G-A
• rs769912149
• NM_012183.3:c.826G>A

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.97
• Publications: 0 publications found

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

ENSG00000293613 (HGNC:):

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]

ACMG classification

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

Sel.	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

Sel.	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.: 32

GnomAD4 exome AF: 7.76e-7 AC: 1 AN: 1289274 Hom.: 0 Cov.: 33 AF XY: 0.00000158 AC XY: 1 AN XY: 633564

African (AFR) AF: 0.0000400 AC: 1 AN: 24984

American (AMR) AF: 0.00 AC: 0 AN: 14032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19482

East Asian (EAS) AF: 0.00 AC: 0 AN: 29768

South Asian (SAS) AF: 0.00 AC: 0 AN: 62764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3608

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1038514

Other (OTH) AF: 0.00 AC: 0 AN: 52776

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	0.14
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	0.97	L
PhyloP100		4.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.46
Sift	Benign	0.051	T
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.27
MutPred		0.31		Gain of glycosylation at G276 (P = 0.0011)
MVP		0.79
ClinPred		0.90	D
GERP RS		2.4
Varity_R		0.34
gMVP		0.78
Mutation Taster		=27/73	disease causing

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

Other links and lift over

dbSNP: rs769912149; hg19: chr1-63789555;