9-116811-C-T

Variant names:

• chr9-116811-C-T
• rs370289268
• NM_207305.5:c.1309G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_207305.5(FOXD4):​c.1309G>A​(p.Gly437Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,599,776 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: 𝑓 0.0000066 (0 hom., cov: 37)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: FOXD4 NM_207305.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.928
• Publications: 0 publications found

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]

ENSG00000302830 (HGNC:):

ACMG classification

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=0.044624537).

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>A	p.Gly437Arg	missense	Exon 1 of 1	NP_997188.2	Q12950

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXD4	ENST00000382500.4	TSL:6 MANE Select	c.1309G>A	p.Gly437Arg	missense	Exon 1 of 1	ENSP00000371940.2	Q12950
	ENSG00000302830	ENST00000789896.1		n.699+1409C>T		intron	N/A
	ENSG00000302830	ENST00000789897.1		n.687+1409C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152278 Hom.: 0 Cov.: 37

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000251 AC: 6 AN: 239380 AF XY: 0.00000766

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: 0.0000104 AC: 15 AN: 1447498 Hom.: 0 Cov.: 46 AF XY: 0.00000696 AC XY: 5 AN XY: 718672

African (AFR) AF: 0.00 AC: 0 AN: 32960

American (AMR) AF: 0.00 AC: 0 AN: 44028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25350

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.000154 AC: 13 AN: 84612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4070

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105356

Other (OTH) AF: 0.0000336 AC: 2 AN: 59602

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152278 Hom.: 0 Cov.: 37 AF XY: 0.0000134 AC XY: 1 AN XY: 74400

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000333 AC: 4

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	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0056	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.35	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.93
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.16		Gain of methylation at G437 (P = 0.0375)
MVP		0.20
ClinPred		0.027	T
GERP RS		-3.9
Varity_R		0.098
gMVP		0.042
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs370289268; hg19: chr9-116811;