Variant chr1-63323453-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012183.3(FOXD3):c.395C>A(p.Pro132Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,453,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

FOXD3
NM_012183.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.702

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16014162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FOXD3	NM_012183.3 linkuse as main transcript	c.395C>A	p.Pro132Gln	missense_variant	1/1	ENST00000371116.4	NP_036315.1
FOXD3-AS1	NR_121637.1 linkuse as main transcript	n.87+902G>T		intron_variant, non_coding_transcript_variant
FOXD3-AS1	NR_121636.1 linkuse as main transcript	n.185+38G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
FOXD3	ENST00000371116.4 linkuse as main transcript	c.395C>A	p.Pro132Gln	missense_variant	1/1		NM_012183.3	ENSP00000360157	P1
FOXD3-AS1	ENST00000427268.1 linkuse as main transcript	n.87+902G>T		intron_variant, non_coding_transcript_variant		1
FOXD3-AS1	ENST00000431294.7 linkuse as main transcript	n.286+38G>T		intron_variant, non_coding_transcript_variant		1
FOXD3-AS1	ENST00000697579.1 linkuse as main transcript	n.203+20G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1453260

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723042

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.395C>A (p.P132Q) alteration is located in exon 1 (coding exon 1) of the FOXD3 gene. This alteration results from a C to A substitution at nucleotide position 395, causing the proline (P) at amino acid position 132 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.26

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.55

MutationTaster

Benign

0.89

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.21

REVEL

Benign

0.14

Sift

Benign

0.24

Sift4G

Benign

0.72

Polyphen

0.080

Vest4

0.12

MutPred

0.22

Loss of glycosylation at P132 (P = 0.0191);

MVP

0.55

ClinPred

0.20

GERP RS

2.6

Varity_R

0.098

gMVP

0.46

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over