1-47438443-C-A

Variant names:

• chr1-47438443-C-A
• rs1486440464
• NM_004474.4:c.308C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004474.4(FOXD2):​c.308C>A​(p.Ala103Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 923,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. A103G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: FOXD2 NM_004474.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.134
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17800882).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004474.4. 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
	FOXD2	NM_004474.4	MANE Select	c.308C>A	p.Ala103Glu	missense	Exon 1 of 1	NP_004465.3	O60548

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXD2	ENST00000334793.6	TSL:6 MANE Select	c.308C>A	p.Ala103Glu	missense	Exon 1 of 1	ENSP00000335493.6	O60548

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000217 AC: 2 AN: 923440 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 431928

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

African (AFR) AF: 0.0000563 AC: 1 AN: 17768

American (AMR) AF: 0.00 AC: 0 AN: 3348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7522

East Asian (EAS) AF: 0.00 AC: 0 AN: 10218

South Asian (SAS) AF: 0.00 AC: 0 AN: 18000

European-Finnish (FIN) AF: 0.0000558 AC: 1 AN: 17928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2036

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 814334

Other (OTH) AF: 0.00 AC: 0 AN: 32286

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	14
DANN	Benign	0.63
DEOGEN2	Benign	0.042	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.13
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.34	N
REVEL	Uncertain	0.35
Sift	Benign	0.097	T
Sift4G	Benign	0.61	T
Polyphen		0.0010	B
Vest4		0.19
MutPred		0.30		Gain of loop (P = 0.0166)
MVP		0.39
ClinPred		0.12	T
GERP RS		-1.7
PromoterAI		0.053	Neutral
Varity_R		0.20
gMVP		0.33
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1486440464; hg19: chr1-47904115;