Genetic Variant FOXD4:p.Gly437Arg (chr9-116811-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_207305.5(FOXD4):c.1309G>C(p.Gly437Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G437W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 37)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FOXD4
NM_207305.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.928

Publications

0 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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.066909224).

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.1309G>C	p.Gly437Arg	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.1309G>C	p.Gly437Arg	missense	Exon 1 of 1	ENSP00000371940.2	Q12950
ENSG00000302830	ENST00000789896.1		n.699+1409C>G		intron	N/A
ENSG00000302830	ENST00000789897.1		n.687+1409C>G		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447498

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718672

show subpopulations

African (AFR)

AF:

0.0000303

AC:

AN:

32960

American (AMR)

AF:

0.00

AC:

AN:

44028

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25350

East Asian (EAS)

AF:

0.00

AC:

AN:

39588

South Asian (SAS)

AF:

0.00

AC:

AN:

84612

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51932

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4070

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105356

Other (OTH)

AF:

0.00

AC:

AN:

59602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0056

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.35

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.067

MetaSVM

Benign

-0.38

MutationAssessor

Benign

0.0

PhyloP100

-0.93

PrimateAI

Benign

0.40

PROVEAN

Benign

0.23

REVEL

Benign

0.21

Sift

Pathogenic

0.0

Sift4G

Benign

0.33

Polyphen

0.0

Vest4

0.11

MutPred

0.16

Gain of methylation at G437 (P = 0.0375)

MVP

0.20

ClinPred

0.057

GERP RS

-3.9

Varity_R

0.098

gMVP

0.042

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over