NM_005169.4:c.752T>A

Variant names:

• chr11-72239852-A-T
• NM_005169.4:c.752T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005169.4(PHOX2A):​c.752T>A​(p.Leu251His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 5.79
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

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.752T>A	p.Leu251His	missense	Exon 3 of 3	NP_005160.2
	PHOX2A	NM_001425096.1		c.836T>A	p.Leu279His	missense	Exon 3 of 3	NP_001412025.1
	PHOX2A	NM_001425097.1		c.776T>A	p.Leu259His	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.752T>A	p.Leu251His	missense	Exon 3 of 3	ENSP00000298231.5	O14813
	PHOX2A	ENST00000546310.1	TSL:5	c.152T>A	p.Leu51His	missense	Exon 2 of 2	ENSP00000444845.1	H0YGU5
	PHOX2A	ENST00000544057.1	TSL:3	n.*15T>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1234084 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 601628

African (AFR) AF: 0.00 AC: 0 AN: 25762

American (AMR) AF: 0.00 AC: 0 AN: 20804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19546

East Asian (EAS) AF: 0.00 AC: 0 AN: 27978

South Asian (SAS) AF: 0.00 AC: 0 AN: 52970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3622

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 990574

Other (OTH) AF: 0.00 AC: 0 AN: 49598

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Benign	0.95
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.9	L
PhyloP100		5.8
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.038	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.35		Loss of stability (P = 0.0786)
MVP		0.98
ClinPred		0.93	D
GERP RS		4.9
Varity_R		0.49
gMVP		0.69
Mutation Taster		=46/54	disease causing

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: chr11-71950896;