1-47438170-C-T

Variant names:

• chr1-47438170-C-T
• rs1646984671
• NM_004474.4:c.35C>T

Variant summary

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

The NM_004474.4(FOXD2):​c.35C>T​(p.Ser12Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXD2 NM_004474.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD2	NM_004474.4	c.35C>T	p.Ser12Phe	missense_variant	Exon 1 of 1	ENST00000334793.6	NP_004465.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXD2	ENST00000334793.6	c.35C>T	p.Ser12Phe	missense_variant	Exon 1 of 1	6	NM_004474.4	ENSP00000335493.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35C>T (p.S12F) 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 35, causing the serine (S) at amino acid position 12 to be replaced by a phenylalanine (F). 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	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	1.0	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	0.81	L
PhyloP100		2.2
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.16
MutPred		0.30		Loss of disorder (P = 0.0097);
MVP		0.99
ClinPred		0.94	D
GERP RS		4.0
PromoterAI		-0.019	Neutral
Varity_R		0.44
gMVP		0.27
Mutation Taster		=60/40	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: rs1646984671; hg19: chr1-47903842;