4-41746162-C-T

Position:

• chr4-41746162-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003924.4(PHOX2B):​c.590G>A​(p.Gly197Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G197G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHOX2B NM_003924.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 4.50

Genes affected

PHOX2B (HGNC:9143): (paired like homeobox 2B) The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription factor involved in the development of several major noradrenergic neuron populations and the determination of neurotransmitter phenotype. The gene product is linked to enhancement of second messenger-mediated activation of the dopamine beta-hydroylase, c-fos promoters and several enhancers, including cyclic amp-response element and serum-response element. Expansion of a 20 amino acid polyalanine tract in this protein by 5-13 aa has been associated with congenital central hypoventilation syndrome. [provided by RefSeq, Jul 2016]

PHOX2B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHOX2B	NM_003924.4	c.590G>A	p.Gly197Asp	missense_variant	3/3	ENST00000226382.4	NP_003915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4	c.590G>A	p.Gly197Asp	missense_variant	3/3	1	NM_003924.4	ENSP00000226382.2
PHOX2B	ENST00000510424.2	n.411G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The p.G197D variant (also known as c.590G>A), located in coding exon 3 of the PHOX2B gene, results from a G to A substitution at nucleotide position 590. The glycine at codon 197 is replaced by aspartic acid, an amino acid with similar properties. This alteration was reported in a 5-year-old female diagnosed with a metastatic adrenal neuroblastoma and thoracic ganglioneuroblastoma, and was also detected in her father, who was diagnosed with a ganglioneuroblastoma. Family history included three additional individuals with neural crest tumors (McConville C et al. Am. J. Med. Genet. A 2006 Jun;140(12):1297-301). One in vitro functional study showed that transactivation activity of PHOX2B p.G197D was similar to wild-type (Trochet D Hum. Mutat. 2009 Feb;30(2):E421-31). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Neuroblastoma, susceptibility to, 2 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 15, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	23
DANN	Benign	0.83
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.0	L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.56
Sift	Benign	0.051	T
Sift4G	Benign	0.38	T
Polyphen		0.016	B
Vest4		0.81
MutPred		0.72		Loss of glycosylation at S194 (P = 0.0847);
MVP		1.0
MPC		1.4
ClinPred		0.46	T
GERP RS		2.6
Varity_R		0.25
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs104893856; hg19: chr4-41748179; COSMIC: COSV105050800; COSMIC: COSV105050800;