Genetic Variant FOXD2:p.Gly80Val (chr1-47438374-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004474.4(FOXD2):c.239G>T(p.Gly80Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G80D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXD2
NM_004474.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.636

Publications

0 publications found

Variant links:

Genes affected

FOXD2 (HGNC:3803): (forkhead box D2) This gene belongs to the forkhead family of transcription factors which is characterized by a distinct forkhead domain. The specific function of this gene has not yet been determined. [provided by RefSeq, Jul 2008]

FOXD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19646367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD2	NM_004474.4 link	c.239G>T	p.Gly80Val	missense_variant	Exon 1 of 1	ENST00000334793.6	NP_004465.3	O60548

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXD2	ENST00000334793.6 link	c.239G>T	p.Gly80Val	missense_variant	Exon 1 of 1	6	NM_004474.4	ENSP00000335493.6		O60548

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1077946

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

509968

African (AFR)

AF:

0.00

AC:

AN:

22596

American (AMR)

AF:

0.00

AC:

AN:

8130

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13974

East Asian (EAS)

AF:

0.00

AC:

AN:

26098

South Asian (SAS)

AF:

0.00

AC:

AN:

21718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2940

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

917476

Other (OTH)

AF:

0.00

AC:

AN:

43202

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

Nov 12, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.239G>T (p.G80V) alteration is located in exon 1 (coding exon 1) of the FOXD2 gene. This alteration results from a G to T substitution at nucleotide position 239, causing the glycine (G) at amino acid position 80 to be replaced by a valine (V). 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

0.12

BayesDel_addAF

Benign

0.0052

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.094

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.48

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.30

MutationAssessor

Benign

0.55

PhyloP100

0.64

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.0

REVEL

Benign

0.25

Sift

Uncertain

0.0080

Sift4G

Benign

0.14

Polyphen

0.082

Vest4

0.076

MutPred

0.16

Loss of methylation at R83 (P = 0.1053);

MVP

0.86

ClinPred

0.25

GERP RS

3.9

PromoterAI

-0.074

Neutral

(source)

Varity_R

0.23

gMVP

0.36

Mutation Taster

=89/11

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over