Genetic Variant PHOX2A:p.Ala68Pro (chr11-72243803-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_005169.4(PHOX2A):c.202G>C(p.Ala68Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,249,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

PHOX2A
NM_005169.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.359

Variant links:

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]

PHOX2A links:

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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=0.22224352).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2A	NM_005169.4 link	c.202G>C	p.Ala68Pro	missense_variant	Exon 1 of 3	ENST00000298231.5	NP_005160.2	O14813
PHOX2A	NM_001425096.1 link	c.202G>C	p.Ala68Pro	missense_variant	Exon 1 of 3		NP_001412025.1
PHOX2A	NM_001425097.1 link	c.202G>C	p.Ala68Pro	missense_variant	Exon 1 of 3		NP_001412026.1
PHOX2A	NM_001425098.1 link	c.202G>C	p.Ala68Pro	missense_variant	Exon 1 of 3		NP_001412027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOX2A	ENST00000298231.5 link	c.202G>C	p.Ala68Pro	missense_variant	Exon 1 of 3	1	NM_005169.4	ENSP00000298231.5		O14813
PHOX2A	ENST00000544057.1 link	n.85+1777G>C		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000191

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000251

AC:

AN:

3982

Hom.:

AF XY:

0.000526

AC XY:

AN XY:

1900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000451

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000119

AC:

130

AN:

1096964

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

520856

show subpopulations

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:

0.0000420

Gnomad4 NFE exome

AF:

0.000135

Gnomad4 OTH exome

AF:

0.0000679

GnomAD4 genome

AF:

0.000112

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.0000176

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.202G>C (p.A68P) alteration is located in exon 1 (coding exon 1) of the PHOX2A gene. This alteration results from a G to C substitution at nucleotide position 202, causing the alanine (A) at amino acid position 68 to be replaced by a proline (P). 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

0.14

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

-0.022

Eigen_PC

Benign

0.076

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.22

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

1.2

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.38

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.041

Polyphen

0.43

Vest4

0.24

MVP

0.64

ClinPred

0.16

GERP RS

4.3

Varity_R

0.37

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over