NM_012183.3:c.191C>A

Variant names:

• chr1-63323249-C-A
• rs374048887
• NM_012183.3:c.191C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_012183.3(FOXD3):​c.191C>A​(p.Ala64Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 1,520,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: FOXD3 NM_012183.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.884
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08909324).
• BS2: High AC in GnomAd4 at 7 AD gene.

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.191C>A	p.Ala64Glu	missense	Exon 1 of 1	NP_036315.1	Q9UJU5
	FOXD3-AS1	NR_121636.1		n.185+242G>T		intron	N/A
	FOXD3-AS1	NR_121637.1		n.87+1106G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXD3	ENST00000371116.4	TSL:6 MANE Select	c.191C>A	p.Ala64Glu	missense	Exon 1 of 1	ENSP00000360157.2	Q9UJU5
	FOXD3-AS1	ENST00000427268.2	TSL:1	n.196+1106G>T		intron	N/A
	FOXD3-AS1	ENST00000431294.8	TSL:1	n.294+242G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152100 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00000890 AC: 1 AN: 112384 AF XY: 0.00

Gnomad AFR exome AF: 0.000332

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1368038 Hom.: 0 Cov.: 33 AF XY: 0.00000297 AC XY: 2 AN XY: 674408

African (AFR) AF: 0.0000358 AC: 1 AN: 27906

American (AMR) AF: 0.00 AC: 0 AN: 33130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24070

East Asian (EAS) AF: 0.00 AC: 0 AN: 31676

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5026

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067016

Other (OTH) AF: 0.0000176 AC: 1 AN: 56682

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152100 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74302

African (AFR) AF: 0.0000965 AC: 4 AN: 41430

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67996

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.000264 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000243 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.88
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.15
Sift	Benign	0.083	T
Sift4G	Benign	0.76	T
Polyphen		0.013	B
Vest4		0.086
MVP		0.15
ClinPred		0.066	T
GERP RS		0.66
Varity_R		0.13
gMVP		0.096
Mutation Taster		=92/8	polymorphism

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: rs374048887; hg19: chr1-63788920;