1-47438280-C-T

Variant names:

• chr1-47438280-C-T
• rs1335922879
• NM_004474.4:c.145C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004474.4(FOXD2):​c.145C>T​(p.Arg49Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000587 in 1,193,198 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000059 (0 hom.)
• Consequence: FOXD2 NM_004474.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.54
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD2	NM_004474.4	c.145C>T	p.Arg49Trp	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.145C>T	p.Arg49Trp	missense_variant	Exon 1 of 1	6	NM_004474.4	ENSP00000335493.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000587 AC: 7 AN: 1193198 Hom.: 0 Cov.: 30 AF XY: 0.00000173 AC XY: 1 AN XY: 579600

African (AFR) AF: 0.00 AC: 0 AN: 23976

American (AMR) AF: 0.00 AC: 0 AN: 10750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16896

East Asian (EAS) AF: 0.000258 AC: 7 AN: 27174

South Asian (SAS) AF: 0.00 AC: 0 AN: 50282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3678

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 983338

Other (OTH) AF: 0.00 AC: 0 AN: 48312

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.145C>T (p.R49W) 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 145, causing the arginine (R) at amino acid position 49 to be replaced by a tryptophan (W). 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	Benign	0.21
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.063
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	1.0	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.34	N
PhyloP100		3.5
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.26
MutPred		0.23		Loss of methylation at R46 (P = 0.0303);
MVP		0.99
ClinPred		0.85	D
GERP RS		3.0
PromoterAI		0.010	Neutral
Varity_R		0.17
gMVP		0.31
Mutation Taster		=86/14	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: rs1335922879; hg19: chr1-47903952; COSMIC: COSV104641535; COSMIC: COSV104641535;