dbSNP rs140850664: PHOX2A:c.-19G>T (chr11-72244023-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005169.4(PHOX2A):c.-19G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000376 in 266,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000038 ( 0 hom. )

Consequence

PHOX2A
NM_005169.4 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.62

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), 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PHOX2A	NM_005169.4 link	c.-19G>T	5_prime_UTR_variant	Exon 1 of 3	ENST00000298231.5	NP_005160.2	O14813
PHOX2A	NM_001425096.1 link	c.-19G>T	5_prime_UTR_variant	Exon 1 of 3		NP_001412025.1
PHOX2A	NM_001425097.1 link	c.-19G>T	5_prime_UTR_variant	Exon 1 of 3		NP_001412026.1
PHOX2A	NM_001425098.1 link	c.-19G>T	5_prime_UTR_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.-19G>T		5_prime_UTR_variant	Exon 1 of 3	1	NM_005169.4	ENSP00000298231.5		O14813
PHOX2A	ENST00000544057.1 link	n.85+1557G>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000376

AC:

AN:

266062

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

127360

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

5688

American (AMR)

AF:

0.00

AC:

AN:

3240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2710

East Asian (EAS)

AF:

0.00

AC:

AN:

6956

South Asian (SAS)

AF:

0.00

AC:

AN:

6250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

702

European-Non Finnish (NFE)

AF:

0.00000460

AC:

AN:

217330

Other (OTH)

AF:

0.00

AC:

AN:

9824

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

2.6

PromoterAI

-0.0042

Neutral

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over