Genetic Variant FOXD2:p.Arg42His (chr1-47438260-G-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.125G>A(p.Arg42His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,367,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. R42C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

FOXD2
NM_004474.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.195

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=0.23989531).

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD2	NM_004474.4 link	c.125G>A	p.Arg42His	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.125G>A	p.Arg42His	missense_variant	Exon 1 of 1	6	NM_004474.4	ENSP00000335493.6		O60548

Frequencies

GnomAD3 genomes

AF:

0.0000857

AC:

AN:

151626

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

12208

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1215914

Hom.:

Cov.:

AF XY:

0.00000506

AC XY:

AN XY:

592902

show subpopulations

African (AFR)

AF:

0.000330

AC:

AN:

24260

American (AMR)

AF:

0.00

AC:

AN:

12086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17902

East Asian (EAS)

AF:

0.00

AC:

AN:

27324

South Asian (SAS)

AF:

0.00

AC:

AN:

54858

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3500

European-Non Finnish (NFE)

AF:

0.00000702

AC:

AN:

997048

Other (OTH)

AF:

0.00

AC:

AN:

49512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000857

AC:

AN:

151734

Hom.:

Cov.:

AF XY:

0.0000944

AC XY:

AN XY:

74150

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41496

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67778

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.548

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000982

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 24, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.125G>A (p.R42H) 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 125, causing the arginine (R) at amino acid position 42 to be replaced by a histidine (H). 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

0.13

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.033

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.65

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.34

PhyloP100

-0.20

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.13

REVEL

Benign

0.19

Sift

Uncertain

0.010

Sift4G

Benign

0.12

Polyphen

0.92

Vest4

0.069

MutPred

0.23

Loss of methylation at R42 (P = 0.0216);

MVP

0.90

ClinPred

0.21

GERP RS

2.6

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.062

gMVP

0.23

Mutation Taster

=97/3

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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1-47438260-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