chr11-72240079-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005169.4(PHOX2A):c.525C>A(p.Asp175Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,530,490 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

PHOX2A
NM_005169.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.79

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

fibrosis of extraocular muscles, congenital, 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
congenital fibrosis of extraocular muscles
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PHOX2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2376742).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005169.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PHOX2A	NM_005169.4	MANE Select	c.525C>A	p.Asp175Glu	missense	Exon 3 of 3	NP_005160.2
PHOX2A	NM_001425096.1		c.609C>A	p.Asp203Glu	missense	Exon 3 of 3	NP_001412025.1
PHOX2A	NM_001425097.1		c.549C>A	p.Asp183Glu	missense	Exon 3 of 3	NP_001412026.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHOX2A	ENST00000298231.5	TSL:1 MANE Select	c.525C>A	p.Asp175Glu	missense	Exon 3 of 3	ENSP00000298231.5	O14813
PHOX2A	ENST00000546310.1	TSL:5	c.85-160C>A		intron	N/A	ENSP00000444845.1	H0YGU5
PHOX2A	ENST00000544057.1	TSL:3	n.393C>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

127760

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1378476

Hom.:

Cov.:

AF XY:

0.00000882

AC XY:

AN XY:

680072

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31014

American (AMR)

AF:

0.00

AC:

AN:

35312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24902

East Asian (EAS)

AF:

0.00

AC:

AN:

35372

South Asian (SAS)

AF:

0.00

AC:

AN:

78824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35956

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4074

European-Non Finnish (NFE)

AF:

0.0000139

AC:

AN:

1075600

Other (OTH)

AF:

0.00

AC:

AN:

57422

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67954

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.0034

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.16

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.72

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.4

PhyloP100

1.8

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.40

Sift

Benign

0.30

Sift4G

Benign

0.20

Polyphen

0.044

Vest4

0.15

MutPred

0.16

Gain of methylation at K178 (P = 0.0823)

MVP

0.76

ClinPred

0.63

GERP RS

3.9

Varity_R

0.14

gMVP

0.38

Mutation Taster

=62/38

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over