11-72240079-G-C

Variant names:

• chr11-72240079-G-C
• rs773687701
• NM_005169.4:c.525C>G

Variant summary

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

The NM_005169.4(PHOX2A):​c.525C>G​(p.Asp175Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,378,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: PHOX2A NM_005169.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2284511).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2A	NM_005169.4	c.525C>G	p.Asp175Glu	missense_variant	Exon 3 of 3	ENST00000298231.5	NP_005160.2
PHOX2A	NM_001425096.1	c.609C>G	p.Asp203Glu	missense_variant	Exon 3 of 3		NP_001412025.1
PHOX2A	NM_001425097.1	c.549C>G	p.Asp183Glu	missense_variant	Exon 3 of 3		NP_001412026.1
PHOX2A	NM_001425098.1	c.*404C>G		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.525C>G	p.Asp175Glu	missense_variant	Exon 3 of 3	1	NM_005169.4	ENSP00000298231.5
PHOX2A	ENST00000546310.1	c.85-160C>G		intron_variant	Intron 1 of 1	5		ENSP00000444845.1
PHOX2A	ENST00000544057.1	n.393C>G		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000783 AC: 1 AN: 127760 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 70050

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000213

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000435 AC: 6 AN: 1378476 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 680072

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: 0.00000558

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.4	L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.40
Sift	Benign	0.30	T
Sift4G	Benign	0.20	T
Polyphen		0.044	B
Vest4		0.15
MutPred		0.16		Gain of methylation at K178 (P = 0.0823);
MVP		0.76
ClinPred		0.30	T
GERP RS		3.9
Varity_R		0.14
gMVP		0.38

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

LitVar

Other links and lift over

dbSNP: rs773687701; hg19: chr11-71951123;