11-72239771-G-T

Variant names:

• chr11-72239771-G-T
• NM_005169.4:c.833C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005169.4(PHOX2A):​c.833C>A​(p.Ala278Asp) 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: 2.88

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26304746).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2A	NM_005169.4	c.833C>A	p.Ala278Asp	missense_variant	Exon 3 of 3	ENST00000298231.5	NP_005160.2
PHOX2A	NM_001425096.1	c.917C>A	p.Ala306Asp	missense_variant	Exon 3 of 3		NP_001412025.1
PHOX2A	NM_001425097.1	c.857C>A	p.Ala286Asp	missense_variant	Exon 3 of 3		NP_001412026.1
PHOX2A	NM_001425098.1	c.*712C>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.833C>A	p.Ala278Asp	missense_variant	Exon 3 of 3	1	NM_005169.4	ENSP00000298231.5
PHOX2A	ENST00000546310.1	c.233C>A	p.Ala78Asp	missense_variant	Exon 2 of 2	5		ENSP00000444845.1
PHOX2A	ENST00000544057.1	n.*96C>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: 1171506 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 563172

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

Aug 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.833C>A (p.A278D) alteration is located in exon 3 (coding exon 3) of the PHOX2A gene. This alteration results from a C to A substitution at nucleotide position 833, causing the alanine (A) at amino acid position 278 to be replaced by an aspartic acid (D). 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	Uncertain	0.50
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.0032
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.69	N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.021	D
Sift4G	Benign	0.21	T
Polyphen		0.60	P
Vest4		0.23
MutPred		0.30		Gain of relative solvent accessibility (P = 0.0082);
MVP		0.51
ClinPred		0.82	D
GERP RS		3.4
Varity_R		0.51
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr11-71950815;