chr11-72239852-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2A	NM_005169.4	c.752T>A	p.Leu251His	missense_variant	Exon 3 of 3	ENST00000298231.5	NP_005160.2
PHOX2A	NM_001425096.1	c.836T>A	p.Leu279His	missense_variant	Exon 3 of 3		NP_001412025.1
PHOX2A	NM_001425097.1	c.776T>A	p.Leu259His	missense_variant	Exon 3 of 3		NP_001412026.1
PHOX2A	NM_001425098.1	c.*631T>A		3_prime_UTR_variant	Exon 3 of 3		NP_001412027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOX2A	ENST00000298231.5	c.752T>A	p.Leu251His	missense_variant	Exon 3 of 3	1	NM_005169.4	ENSP00000298231.5
PHOX2A	ENST00000546310.1	c.152T>A	p.Leu51His	missense_variant	Exon 2 of 2	5		ENSP00000444845.1
PHOX2A	ENST00000544057.1	n.*15T>A		downstream_gene_variant		3

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

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.752T>A (p.L251H) alteration is located in exon 3 (coding exon 3) of the PHOX2A gene. This alteration results from a T to A substitution at nucleotide position 752, causing the leucine (L) at amino acid position 251 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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
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

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.

Other links and lift over

hg19: chr11-71950896;