dbSNP rs104894269: PHOX2A:p.Ala72Val (chr11-72243790-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001425096.1(PHOX2A):c.215C>T(p.Ala72Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PHOX2A
NM_001425096.1 missense, splice_region

Scores

Splicing: ADA: 0.9947

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 7.13

Publications

3 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), Genomics England PanelApp, G2P
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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001425096.1. 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.215C>T	p.Ala72Val	missense splice_region	Exon 1 of 3	NP_005160.2
PHOX2A	NM_001425096.1		c.215C>T	p.Ala72Val	missense splice_region	Exon 1 of 3	NP_001412025.1
PHOX2A	NM_001425097.1		c.215C>T	p.Ala72Val	missense splice_region	Exon 1 of 3	NP_001412026.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2A	ENST00000298231.5	TSL:1 MANE Select	c.215C>T	p.Ala72Val	missense splice_region	Exon 1 of 3	ENSP00000298231.5
	PHOX2A	ENST00000544057.1	TSL:3	n.85+1790C>T		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1095328

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

520086

African (AFR)

AF:

0.00

AC:

AN:

23016

American (AMR)

AF:

0.00

AC:

AN:

8516

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14592

East Asian (EAS)

AF:

0.00

AC:

AN:

26566

South Asian (SAS)

AF:

0.00

AC:

AN:

25590

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22984

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2956

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

926974

Other (OTH)

AF:

0.00

AC:

AN:

44134

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fibrosis of extraocular muscles, congenital, 2 (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.82

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

0.90

PhyloP100

7.1

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.64

Sift

Uncertain

0.017

Sift4G

Benign

0.10

Polyphen

0.63

Vest4

0.70

MutPred

0.73

Loss of disorder (P = 0.066)

MVP

0.90

ClinPred

0.93

GERP RS

4.4

PromoterAI

0.13

Neutral

(source)

Varity_R

0.21

gMVP

0.50

Mutation Taster

=25/75

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.80

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.99

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over