Genetic Variant PHOX2A:p.Ala230Val (chr11-72239915-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005169.4(PHOX2A):c.689C>T(p.Ala230Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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_005169.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.33

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3256197).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2A	NM_005169.4 link	c.689C>T	p.Ala230Val	missense_variant	Exon 3 of 3	ENST00000298231.5	NP_005160.2	O14813
PHOX2A	NM_001425096.1 link	c.773C>T	p.Ala258Val	missense_variant	Exon 3 of 3		NP_001412025.1
PHOX2A	NM_001425097.1 link	c.713C>T	p.Ala238Val	missense_variant	Exon 3 of 3		NP_001412026.1
PHOX2A	NM_001425098.1 link	c.*568C>T		3_prime_UTR_variant	Exon 3 of 3		NP_001412027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PHOX2A	ENST00000298231.5 link	c.689C>T	p.Ala230Val	missense_variant	Exon 3 of 3	1	NM_005169.4	ENSP00000298231.5	O14813
PHOX2A	ENST00000546310.1 link	c.89C>T	p.Ala30Val	missense_variant	Exon 2 of 2	5		ENSP00000444845.1	H0YGU5
PHOX2A	ENST00000544057.1 link	n.557C>T		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

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

AF:

0.00

AC:

AN:

1159698

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

557706

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

PHOX2A-related disorder

Uncertain:1

Jun 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PHOX2A c.689C>T variant is predicted to result in the amino acid substitution p.Ala230Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.67

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.35

MutationAssessor

Benign

0.55

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.97

REVEL

Uncertain

0.31

Sift

Benign

0.22

Sift4G

Benign

0.32

Polyphen

0.089

Vest4

0.23

MutPred

0.34

Gain of sheet (P = 0.0043);

MVP

0.84

ClinPred

0.49

GERP RS

4.0

Varity_R

0.14

gMVP

0.29

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over