Genetic Variant FOXD2:p.Arg46Cys (chr1-47438271-C-T) – 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.136C>T(p.Arg46Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000477 in 1,357,540 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★).

Frequency

Genomes: 𝑓 0.00047 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 0 hom. )

Consequence

FOXD2
NM_004474.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.840

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=0.20710778).

BS2

High AC in GnomAd4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD2	NM_004474.4 link	c.136C>T	p.Arg46Cys	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.136C>T	p.Arg46Cys	missense_variant	Exon 1 of 1	6	NM_004474.4	ENSP00000335493.6		O60548

Frequencies

GnomAD3 genomes

AF:

0.000475

AC:

AN:

151670

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000191

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000118

AC:

AN:

8458

AF XY:

0.00

show subpopulations

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:

0.000333

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000478

AC:

576

AN:

1205870

Hom.:

Cov.:

AF XY:

0.000499

AC XY:

293

AN XY:

586856

show subpopulations

African (AFR)

AF:

0.0000414

AC:

AN:

24170

American (AMR)

AF:

0.000261

AC:

AN:

11494

Ashkenazi Jewish (ASJ)

AF:

0.0000577

AC:

AN:

17342

East Asian (EAS)

AF:

0.00

AC:

AN:

27270

South Asian (SAS)

AF:

0.00

AC:

AN:

52776

European-Finnish (FIN)

AF:

0.000274

AC:

AN:

29148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3720

European-Non Finnish (NFE)

AF:

0.000556

AC:

551

AN:

990976

Other (OTH)

AF:

0.000245

AC:

AN:

48974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

102

136

170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000475

AC:

AN:

151670

Hom.:

Cov.:

AF XY:

0.000527

AC XY:

AN XY:

74050

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41378

American (AMR)

AF:

0.00

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.000191

AC:

AN:

10478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00103

AC:

AN:

67804

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00140

Hom.:

Bravo

AF:

0.000419

ExAC

AF:

0.000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 21, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.136C>T (p.R46C) alteration is located in exon 1 (coding exon 1) of the FOXD2 gene. This alteration results from a C to T substitution at nucleotide position 136, causing the arginine (R) at amino acid position 46 to be replaced by a cysteine (C). 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

0.22

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.036

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.70

M_CAP

Pathogenic

1.0

MetaRNN

Benign

0.21

MetaSVM

Uncertain

-0.056

MutationAssessor

Benign

0.0

PhyloP100

0.84

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-0.56

REVEL

Benign

0.27

Sift

Benign

0.14

Sift4G

Uncertain

0.056

Polyphen

0.99

Vest4

0.21

MVP

0.90

ClinPred

0.13

GERP RS

2.3

PromoterAI

0.040

Neutral

(source)

Varity_R

0.078

gMVP

0.34

Mutation Taster

=88/12

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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1-47438271-C-T

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