Genetic Variant FOXB1:p.Asp115Glu (chr15-60005308-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012182.3(FOXB1):c.345C>G(p.Asp115Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

FOXB1
NM_012182.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.103

Variant links:

Genes affected

FOXB1 (HGNC:3799): (forkhead box B1) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in several processes, including mammary gland development; nervous system development; and visual learning. Predicted to act upstream of or within spinal cord development; thalamus development; and urogenital system development. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

FOXB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07399216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXB1	NM_012182.3 link	c.345C>G	p.Asp115Glu	missense_variant	Exon 2 of 2	ENST00000396057.6	NP_036314.2	Q99853

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXB1	ENST00000396057.6 link	c.345C>G	p.Asp115Glu	missense_variant	Exon 2 of 2	1	NM_012182.3	ENSP00000379369.4		Q99853
FOXB1	ENST00000560857.1 link	n.410+665C>G		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152218

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

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

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.345C>G (p.D115E) alteration is located in exon 2 (coding exon 1) of the FOXB1 gene. This alteration results from a C to G substitution at nucleotide position 345, causing the aspartic acid (D) at amino acid position 115 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

0.10

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.16

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.72

M_CAP

Benign

0.036

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.41

MutationAssessor

Benign

0.53

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.44

REVEL

Uncertain

0.33

Sift

Benign

0.72

Sift4G

Benign

0.48

Polyphen

0.0010

Vest4

0.029

MutPred

0.20

Loss of MoRF binding (P = 0.1216);

MVP

0.51

MPC

0.79

ClinPred

0.11

GERP RS

1.8

Varity_R

0.061

gMVP

0.65

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over