11-72240009-C-T

Position:

• chr11-72240009-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000298231.5(PHOX2A):​c.595G>A​(p.Gly199Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000786 in 1,272,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: 7.9e-7 (0 hom.)
• Consequence: PHOX2A ENST00000298231.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0310

Genes affected

PHOX2A (HGNC:691): (paired like homeobox 2A) The protein encoded by this gene contains a paired-like homeodomain most similar to that of the Drosophila aristaless gene product. The encoded protein plays a central role in development of the autonomic nervous system. It regulates the expression of tyrosine hydroxylase and dopamine beta-hydroxylase, two catecholaminergic biosynthetic enzymes essential for the differentiation and maintenance of the noradrenergic neurotransmitter phenotype. The encoded protein has also been shown to regulate transcription of the alpha3 nicotinic acetylcholine receptor gene. Mutations in this gene have been associated with autosomal recessive congenital fibrosis of the extraocular muscles. [provided by RefSeq, Jul 2008]

ACMG classification

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=0.07087004).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHOX2A	NM_005169.4	c.595G>A	p.Gly199Ser	missense_variant	3/3	ENST00000298231.5	NP_005160.2
PHOX2A	XM_047426947.1	c.679G>A	p.Gly227Ser	missense_variant	3/3		XP_047282903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHOX2A	ENST00000298231.5	c.595G>A	p.Gly199Ser	missense_variant	3/3	1	NM_005169.4	ENSP00000298231	P1
PHOX2A	ENST00000546310.1	c.86-90G>A		intron_variant		5		ENSP00000444845
PHOX2A	ENST00000544057.1	n.463G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.86e-7 AC: 1 AN: 1272992 Hom.: 0 Cov.: 31 AF XY: 0.00000160 AC XY: 1 AN XY: 624984

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.75e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2021

The c.595G>A (p.G199S) alteration is located in exon 3 (coding exon 3) of the PHOX2A gene. This alteration results from a G to A substitution at nucleotide position 595, causing the glycine (G) at amino acid position 199 to be replaced by a serine (S). 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	0.078
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.27	N
REVEL	Benign	0.16
Sift	Benign	0.67	T
Sift4G	Benign	0.42	T
Polyphen		0.0030	B
Vest4		0.12
MutPred		0.34		Gain of phosphorylation at G199 (P = 0.0026);
MVP		0.44
ClinPred		0.062	T
GERP RS		1.8
Varity_R		0.027
gMVP		0.16

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: rs1476578050; hg19: chr11-71951053; COSMIC: COSV105141969; COSMIC: COSV105141969;