9-77020217-C-A

Variant names:

• chr9-77020217-C-A
• rs544997803
• NM_001013735.1:c.563C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001013735.1(FOXB2):​c.563C>A​(p.Pro188Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000966 in 1,035,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P188R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 9.7e-7 (0 hom.)
• Consequence: FOXB2 NM_001013735.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.215
• Publications: 0 publications found

Genes affected

FOXB2 (HGNC:23315): (forkhead box B2) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in anatomical structure morphogenesis; cell differentiation; and regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

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=0.12587684).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013735.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXB2	NM_001013735.1	MANE Select	c.563C>A	p.Pro188Gln	missense	Exon 1 of 1	NP_001013757.1	Q5VYV0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXB2	ENST00000376708.1	TSL:6 MANE Select	c.563C>A	p.Pro188Gln	missense	Exon 1 of 1	ENSP00000365898.1	Q5VYV0
	FOXB2	ENST00000850987.1		c.563C>A	p.Pro188Gln	missense	Exon 1 of 1	ENSP00000521069.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 9.66e-7 AC: 1 AN: 1035614 Hom.: 0 Cov.: 15 AF XY: 0.00000187 AC XY: 1 AN XY: 533848

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

African (AFR) AF: 0.00 AC: 0 AN: 25430

American (AMR) AF: 0.00 AC: 0 AN: 44134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23510

East Asian (EAS) AF: 0.00 AC: 0 AN: 37812

South Asian (SAS) AF: 0.00 AC: 0 AN: 78132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4916

European-Non Finnish (NFE) AF: 0.00000136 AC: 1 AN: 736914

Other (OTH) AF: 0.00 AC: 0 AN: 46642

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.38	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.21
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.028
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.14	T
Polyphen		0.31	B
Vest4		0.22
MutPred		0.26		Loss of glycosylation at P188 (P = 0.0331)
MVP		0.55
ClinPred		0.24	T
GERP RS		3.4
Varity_R		0.21
gMVP		0.33
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs544997803; hg19: chr9-79635133;