rs1274354686

Variant names:

• chr1-47438333-C-G
• rs1274354686
• NM_004474.4:c.198C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-47438333-C-G
• chr1-47438333-C-T

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.198C>G​(p.Asp66Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000233 in 1,285,152 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: FOXD2 NM_004474.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.527
• 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=0.20800352).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD2	NM_004474.4	c.198C>G	p.Asp66Glu	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.198C>G	p.Asp66Glu	missense_variant	Exon 1 of 1	6	NM_004474.4	ENSP00000335493.6

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151546 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000176 AC: 2 AN: 1133606 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 543318

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

African (AFR) AF: 0.0000433 AC: 1 AN: 23108

American (AMR) AF: 0.00 AC: 0 AN: 8596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15200

East Asian (EAS) AF: 0.00 AC: 0 AN: 26566

South Asian (SAS) AF: 0.00 AC: 0 AN: 37384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3408

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 947328

Other (OTH) AF: 0.0000220 AC: 1 AN: 45468

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151546 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73996

African (AFR) AF: 0.0000242 AC: 1 AN: 41350

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67840

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.198C>G (p.D66E) alteration is located in exon 1 (coding exon 1) of the FOXD2 gene. This alteration results from a C to G substitution at nucleotide position 198, causing the aspartic acid (D) at amino acid position 66 to be replaced by a glutamic acid (E). 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	0.091
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.50
DEOGEN2	Benign	0.037	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.35	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.53
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.17
Sift	Benign	0.42	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.085
MutPred		0.24		Gain of helix (P = 0.1736);
MVP		0.84
ClinPred		0.064	T
GERP RS		1.4
PromoterAI		0.0032	Neutral
Varity_R		0.036
gMVP		0.11
Mutation Taster		=98/2	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: rs1274354686; hg19: chr1-47904005;