11-72239915-G-A

Variant names:

• chr11-72239915-G-A
• NM_005169.4:c.689C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33
• Publications: 0 publications found

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

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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

Sel.	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.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1159698 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 557706

African (AFR) AF: 0.00 AC: 0 AN: 23654

American (AMR) AF: 0.00 AC: 0 AN: 10308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15808

East Asian (EAS) AF: 0.00 AC: 0 AN: 27028

South Asian (SAS) AF: 0.00 AC: 0 AN: 36002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3148

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 957888

Other (OTH) AF: 0.00 AC: 0 AN: 46456

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	PHOX2A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.3
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.31
Sift	Benign	0.22	T
Sift4G	Benign	0.32	T
Polyphen		0.089	B
Vest4		0.23
MutPred		0.34		Gain of sheet (P = 0.0043)
MVP		0.84
ClinPred		0.49	T
GERP RS		4.0
Varity_R		0.14
gMVP		0.29
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

hg19: chr11-71950959;