Genetic Variant FOXD4:p.Gly416Arg (chr9-116874-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_StrongBP6_Moderate

The NM_207305.5(FOXD4):c.1246G>A(p.Gly416Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000435 in 1,610,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

FOXD4
NM_207305.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.95

Publications

2 publications found

Variant links:

Genes affected

FOXD4 (HGNC:3805): (forkhead box D4) This gene encodes a member of the forkhead/winged helix-box (FOX) family of transcription factors. FOX transcription factors play critical roles in the regulation of multiple processes including metabolism, cell proliferation and gene expression during ontogenesis. Mutations in this gene are associated with a complex phenotype consisting of dilated cardiomyopathy, obsessive-compulsive disorders, and suicidality. [provided by RefSeq, Mar 2012]

FOXD4 links:

ENSG00000302830 (HGNC:):

ENSG00000302830 links:

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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=0.010917485).

BP6

Variant 9-116874-C-T is Benign according to our data. Variant chr9-116874-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3516637.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207305.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXD4	NM_207305.5	MANE Select	c.1246G>A	p.Gly416Arg	missense	Exon 1 of 1	NP_997188.2	Q12950

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXD4	ENST00000382500.4	TSL:6 MANE Select	c.1246G>A	p.Gly416Arg	missense	Exon 1 of 1	ENSP00000371940.2	Q12950
ENSG00000302830	ENST00000789896.1		n.699+1472C>T		intron	N/A
ENSG00000302830	ENST00000789897.1		n.687+1472C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000527

AC:

AN:

246620

AF XY:

0.0000373

show subpopulations

Gnomad AFR exome

AF:

0.000743

Gnomad AMR exome

AF:

0.0000580

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:

0.0000233

AC:

AN:

1457798

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

724918

show subpopulations

African (AFR)

AF:

0.000540

AC:

AN:

33306

American (AMR)

AF:

0.0000673

AC:

AN:

44598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26052

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86026

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53254

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110694

Other (OTH)

AF:

0.000183

AC:

AN:

60086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000236

AC:

AN:

152390

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74532

show subpopulations

African (AFR)

AF:

0.000793

AC:

AN:

41598

American (AMR)

AF:

0.000196

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000869

Hom.:

Bravo

AF:

0.000242

ESP6500AA

AF:

0.000458

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000578

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.46

CADD

Benign

4.2

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0029

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.41

M_CAP

Benign

0.042

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.14

PhyloP100

-2.9

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.20

REVEL

Benign

0.23

Sift

Benign

0.73

Sift4G

Benign

0.98

Polyphen

0.0040

Vest4

0.073

MutPred

0.070

Gain of solvent accessibility (P = 0.019)

MVP

0.12

ClinPred

0.022

GERP RS

-4.8

Varity_R

0.034

gMVP

0.024

Mutation Taster

=99/1

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over