Genetic Variant NM_005169.4:c.689C>T (chr11-72239915-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

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.689C>T	p.Ala230Val	missense	Exon 3 of 3	NP_005160.2
PHOX2A	NM_001425096.1		c.773C>T	p.Ala258Val	missense	Exon 3 of 3	NP_001412025.1
PHOX2A	NM_001425097.1		c.713C>T	p.Ala238Val	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.689C>T	p.Ala230Val	missense	Exon 3 of 3	ENSP00000298231.5	O14813
PHOX2A	ENST00000546310.1	TSL:5	c.89C>T	p.Ala30Val	missense	Exon 2 of 2	ENSP00000444845.1	H0YGU5
PHOX2A	ENST00000544057.1	TSL:3	n.557C>T		non_coding_transcript_exon	Exon 3 of 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

African (AFR)

AF:

0.00

AC:

AN:

23654

American (AMR)

AF:

0.00

AC:

AN:

10308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15808

East Asian (EAS)

AF:

0.00

AC:

AN:

27028

South Asian (SAS)

AF:

0.00

AC:

AN:

36002

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3148

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

957888

Other (OTH)

AF:

0.00

AC:

AN:

46456

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

PHOX2A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

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

PhyloP100

3.3

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

Mutation Taster

=86/14

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over