Genetic Variant FOXD2:p.Ala65Thr (chr1-47438328-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004474.4(FOXD2):c.193G>A(p.Ala65Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0652 in 1,292,970 control chromosomes in the GnomAD database, including 3,772 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.068 ( 486 hom., cov: 32)

Exomes 𝑓: 0.065 ( 3286 hom. )

Consequence

FOXD2
NM_004474.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.18

Publications

11 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020410717).

BP6

Variant 1-47438328-G-A is Benign according to our data. Variant chr1-47438328-G-A is described in ClinVar as [Benign]. Clinvar id is 667745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD2	NM_004474.4 link	c.193G>A	p.Ala65Thr	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.193G>A	p.Ala65Thr	missense_variant	Exon 1 of 1	6	NM_004474.4	ENSP00000335493.6		O60548

Frequencies

GnomAD3 genomes

AF:

0.0678

AC:

10273

AN:

151482

Hom.:

490

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0594

Gnomad AMI

AF:

0.124

Gnomad AMR

AF:

0.0692

Gnomad ASJ

AF:

0.0620

Gnomad EAS

AF:

0.175

Gnomad SAS

AF:

0.211

Gnomad FIN

AF:

0.0513

Gnomad MID

AF:

0.0764

Gnomad NFE

AF:

0.0565

Gnomad OTH

AF:

0.0656

GnomAD2 exomes

AF:

0.0919

AC:

164

AN:

1784

AF XY:

0.0963

show subpopulations

Gnomad AFR exome

AF:

0.0577

Gnomad AMR exome

AF:

0.122

Gnomad ASJ exome

AF:

0.0789

Gnomad EAS exome

AF:

0.389

Gnomad FIN exome

AF:

0.0426

Gnomad NFE exome

AF:

0.0678

Gnomad OTH exome

AF:

0.100

GnomAD4 exome

AF:

0.0649

AC:

74051

AN:

1141380

Hom.:

3286

Cov.:

AF XY:

0.0670

AC XY:

36727

AN XY:

548272

show subpopulations

African (AFR)

AF:

0.0556

AC:

1289

AN:

23176

American (AMR)

AF:

0.0637

AC:

555

AN:

8714

Ashkenazi Jewish (ASJ)

AF:

0.0614

AC:

943

AN:

15362

East Asian (EAS)

AF:

0.218

AC:

5816

AN:

26690

South Asian (SAS)

AF:

0.207

AC:

8234

AN:

39768

European-Finnish (FIN)

AF:

0.0488

AC:

1316

AN:

26988

Middle Eastern (MID)

AF:

0.0860

AC:

295

AN:

3432

European-Non Finnish (NFE)

AF:

0.0549

AC:

52239

AN:

951466

Other (OTH)

AF:

0.0735

AC:

3364

AN:

45784

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

3915

7829

11744

15658

19573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0677

AC:

10266

AN:

151590

Hom.:

486

Cov.:

AF XY:

0.0720

AC XY:

5332

AN XY:

74076

show subpopulations

African (AFR)

AF:

0.0594

AC:

2460

AN:

41430

American (AMR)

AF:

0.0691

AC:

1054

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0620

AC:

215

AN:

3466

East Asian (EAS)

AF:

0.175

AC:

887

AN:

5080

South Asian (SAS)

AF:

0.211

AC:

1015

AN:

4816

European-Finnish (FIN)

AF:

0.0513

AC:

533

AN:

10388

Middle Eastern (MID)

AF:

0.0685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0565

AC:

3832

AN:

67838

Other (OTH)

AF:

0.0649

AC:

137

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

460

921

1381

1842

2302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0645

Hom.:

397

Bravo

AF:

0.0661

TwinsUK

AF:

0.0518

AC:

192

ALSPAC

AF:

0.0524

AC:

202

ExAC

AF:

0.0349

AC:

576

Asia WGS

AF:

0.147

AC:

506

AN:

3444

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 18, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.024

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

PhyloP100

1.2

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

0.20

REVEL

Benign

0.14

Sift

Benign

0.090

Sift4G

Benign

0.58

Polyphen

0.037

Vest4

0.051

ClinPred

0.0066

GERP RS

4.1

PromoterAI

0.027

Neutral

(source)

Varity_R

0.077

gMVP

0.14

Mutation Taster

=91/9

polymorphism (auto)

(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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1-47438328-G-A

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