dbSNP rs964252467: FOXD2:p.Pro97Thr (chr1-47438424-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004474.4(FOXD2):c.289C>A(p.Pro97Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,143,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

FOXD2
NM_004474.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.849

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19551802).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD2	NM_004474.4 link	c.289C>A	p.Pro97Thr	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.289C>A	p.Pro97Thr	missense_variant	Exon 1 of 1	6	NM_004474.4	ENSP00000335493.6		O60548

Frequencies

GnomAD3 genomes

AF:

0.0000411

AC:

AN:

146050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000199

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000609

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000129

AC:

129

AN:

997538

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

469148

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20120

American (AMR)

AF:

0.00

AC:

AN:

5734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10596

East Asian (EAS)

AF:

0.00

AC:

AN:

19786

South Asian (SAS)

AF:

0.000373

AC:

AN:

18758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

17118

Middle Eastern (MID)

AF:

0.000408

AC:

AN:

2450

European-Non Finnish (NFE)

AF:

0.000136

AC:

118

AN:

865304

Other (OTH)

AF:

0.0000796

AC:

AN:

37672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000411

AC:

AN:

146050

Hom.:

Cov.:

AF XY:

0.0000563

AC XY:

AN XY:

71066

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40784

American (AMR)

AF:

0.00

AC:

AN:

14748

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3284

East Asian (EAS)

AF:

0.000199

AC:

AN:

5022

South Asian (SAS)

AF:

0.000208

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000609

AC:

AN:

65658

Other (OTH)

AF:

0.00

AC:

AN:

2022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.289C>A (p.P97T) alteration is located in exon 1 (coding exon 1) of the FOXD2 gene. This alteration results from a C to A substitution at nucleotide position 289, causing the proline (P) at amino acid position 97 to be replaced by a threonine (T). 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

0.088

BayesDel_addAF

Benign

-0.00034

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.073

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.45

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.39

MutationAssessor

Benign

0.69

PhyloP100

0.85

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.34

Sift

Benign

0.090

Sift4G

Benign

0.34

Polyphen

0.0030

Vest4

0.13

MutPred

0.26

Gain of phosphorylation at P97 (P = 0.0318);

MVP

0.61

ClinPred

0.061

GERP RS

2.4

PromoterAI

-0.068

Neutral

(source)

Varity_R

0.12

gMVP

0.63

Mutation Taster

=85/15

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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rs964252467

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over