rs114453593

Variant names:

• chr1-63323697-C-T
• rs114453593
• NM_012183.3:c.639C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_012183.3(FOXD3):​c.639C>T​(p.Asn213Asn) variant causes a synonymous change. The variant allele was found at a frequency of 0.003 in 1,614,078 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (16 hom.)
• Consequence: FOXD3 NM_012183.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.25
• Publications: 2 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 1-63323697-C-T is Benign according to our data. Variant chr1-63323697-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 775557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 258 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.639C>T	p.Asn213Asn	synonymous	Exon 1 of 1	NP_036315.1	Q9UJU5
	FOXD3-AS1	NR_121637.1		n.87+658G>A		intron	N/A
	FOXD3-AS1	NR_121636.1		n.-22G>A		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.639C>T	p.Asn213Asn	synonymous	Exon 1 of 1	ENSP00000360157.2	Q9UJU5
	FOXD3-AS1	ENST00000431294.8	TSL:1	n.88G>A		non_coding_transcript_exon	Exon 1 of 3
	FOXD3-AS1	ENST00000427268.2	TSL:1	n.196+658G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 258 AN: 152200 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00134 AC: 336 AN: 251278 AF XY: 0.00138

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00257

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00313 AC: 4577 AN: 1461762 Hom.: 16 Cov.: 34 AF XY: 0.00301 AC XY: 2190 AN XY: 727182

African (AFR) AF: 0.000627 AC: 21 AN: 33478

American (AMR) AF: 0.000537 AC: 24 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86246

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00393 AC: 4367 AN: 1111972

Other (OTH) AF: 0.00189 AC: 114 AN: 60390

GnomAD4 genome AF: 0.00169 AC: 258 AN: 152316 Hom.: 3 Cov.: 33 AF XY: 0.00150 AC XY: 112 AN XY: 74472

African (AFR) AF: 0.000433 AC: 18 AN: 41596

American (AMR) AF: 0.00131 AC: 20 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00303 AC: 206 AN: 68020

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00194 Hom.: 0

Bravo AF: 0.00209

EpiCase AF: 0.00251

EpiControl AF: 0.00279

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	14
DANN	Uncertain	0.98
PhyloP100		5.3
Mutation Taster		=41/59	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: rs114453593; hg19: chr1-63789368;