chr1-47438232-G-T

Variant names:

• chr1-47438232-G-T
• rs964816097
• NM_004474.4:c.97G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004474.4(FOXD2):​c.97G>T​(p.Gly33Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000498 in 1,405,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: FOXD2 NM_004474.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3615981).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD2	NM_004474.4	c.97G>T	p.Gly33Cys	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.97G>T	p.Gly33Cys	missense_variant	Exon 1 of 1	6	NM_004474.4	ENSP00000335493.6

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151668 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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

GnomAD2 exomes AF: 0.000139 AC: 5 AN: 35888 AF XY: 0.0000468

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000854

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: 0.00000399 AC: 5 AN: 1254028 Hom.: 0 Cov.: 30 AF XY: 0.00000325 AC XY: 2 AN XY: 615418

African (AFR) AF: 0.00 AC: 0 AN: 25098

American (AMR) AF: 0.000246 AC: 4 AN: 16280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20364

East Asian (EAS) AF: 0.00 AC: 0 AN: 27630

South Asian (SAS) AF: 0.00 AC: 0 AN: 62388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1016400

Other (OTH) AF: 0.0000195 AC: 1 AN: 51334

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151668 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74038

African (AFR) AF: 0.00 AC: 0 AN: 41390

American (AMR) AF: 0.000131 AC: 2 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10486

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67798

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.97G>T (p.G33C) alteration is located in exon 1 (coding exon 1) of the FOXD2 gene. This alteration results from a G to T substitution at nucleotide position 97, causing the glycine (G) at amino acid position 33 to be replaced by a cysteine (C). 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	0.15
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	0.066
Eigen_PC	Benign	0.068
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	0.55	N
PhyloP100		1.6
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.98	D
Vest4		0.26
MutPred		0.36		Loss of phosphorylation at S34 (P = 0.0892);
MVP		0.94
ClinPred		0.26	T
GERP RS		2.7
PromoterAI		-0.041	Neutral
Varity_R		0.30
gMVP		0.21
Mutation Taster		=88/12	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: rs964816097; hg19: chr1-47903904;