Genetic Variant FOXD2:p.His54Asp (chr1-47438295-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004474.4(FOXD2):c.160C>G(p.His54Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000017 in 1,174,664 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: not found (cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

FOXD2
NM_004474.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.411

Publications

0 publications found

Variant links:

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]

FOXD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.112202704).

BS2

High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD2	NM_004474.4 link	c.160C>G	p.His54Asp	missense_variant	Exon 1 of 1	ENST00000334793.6	NP_004465.3	O60548

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXD2	ENST00000334793.6 link	c.160C>G	p.His54Asp	missense_variant	Exon 1 of 1	6	NM_004474.4	ENSP00000335493.6		O60548

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000170

AC:

AN:

1174664

Hom.:

Cov.:

AF XY:

0.0000106

AC XY:

AN XY:

568546

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23722

American (AMR)

AF:

0.00

AC:

AN:

9934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16252

East Asian (EAS)

AF:

0.00

AC:

AN:

26988

South Asian (SAS)

AF:

0.00

AC:

AN:

46578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3628

European-Non Finnish (NFE)

AF:

0.0000206

AC:

AN:

971916

Other (OTH)

AF:

0.00

AC:

AN:

47336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 21, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.160C>G (p.H54D) 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 160, causing the histidine (H) at amino acid position 54 to be replaced by an aspartic acid (D). 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

0.080

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.024

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.41

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.0

PhyloP100

0.41

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

0.22

REVEL

Benign

0.098

Sift

Benign

0.042

Sift4G

Benign

0.39

Polyphen

0.0010

Vest4

0.11

MutPred

0.23

Gain of relative solvent accessibility (P = 0.0098);

MVP

0.26

ClinPred

0.054

GERP RS

-1.6

PromoterAI

-0.099

Neutral

(source)

Varity_R

0.097

gMVP

0.26

Mutation Taster

=86/14

polymorphism

(source)

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

Publications

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1-47438295-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over