Genetic Variant FOXD2:p.Val51Met (chr1-47438286-G-A) – 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.151G>A(p.Val51Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000337 in 1,187,556 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: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

FOXD2
NM_004474.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.309

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=0.15100083).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD2	NM_004474.4 link	c.151G>A	p.Val51Met	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.151G>A	p.Val51Met	missense_variant	Exon 1 of 1	6	NM_004474.4	ENSP00000335493.6		O60548

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000337

AC:

AN:

1187556

Hom.:

Cov.:

AF XY:

0.00000174

AC XY:

AN XY:

576152

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23918

American (AMR)

AF:

0.00

AC:

AN:

10454

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16660

East Asian (EAS)

AF:

0.0000737

AC:

AN:

27124

South Asian (SAS)

AF:

0.00

AC:

AN:

49164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28718

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3552

European-Non Finnish (NFE)

AF:

0.00000102

AC:

AN:

979956

Other (OTH)

AF:

0.0000208

AC:

AN:

48010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.151G>A (p.V51M) alteration is located in exon 1 (coding exon 1) of the FOXD2 gene. This alteration results from a G to A substitution at nucleotide position 151, causing the valine (V) at amino acid position 51 to be replaced by a methionine (M). 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

0.16

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.041

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.53

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.54

MutationAssessor

Benign

0.0

PhyloP100

-0.31

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.14

REVEL

Benign

0.14

Sift

Benign

0.12

Sift4G

Benign

0.22

Polyphen

0.0020

Vest4

0.051

MutPred

0.32

Gain of catalytic residue at V51 (P = 0.0062);

MVP

0.65

ClinPred

0.046

GERP RS

2.1

PromoterAI

0.00010

Neutral

(source)

Varity_R

0.061

gMVP

0.18

Mutation Taster

=82/18

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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1-47438286-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over