chr4-41746072-G-T

Variant names:

• chr4-41746072-G-T
• rs779913205
• NM_003924.4:c.680C>A

Variant summary

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

The NM_003924.4(PHOX2B):​c.680C>A​(p.Ala227Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000156 in 1,280,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: PHOX2B NM_003924.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.365

Genes affected

PHOX2B (HGNC:9143): (paired like homeobox 2B) The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription factor involved in the development of several major noradrenergic neuron populations and the determination of neurotransmitter phenotype. The gene product is linked to enhancement of second messenger-mediated activation of the dopamine beta-hydroylase, c-fos promoters and several enhancers, including cyclic amp-response element and serum-response element. Expansion of a 20 amino acid polyalanine tract in this protein by 5-13 aa has been associated with congenital central hypoventilation syndrome. [provided by RefSeq, Jul 2016]

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=0.08136687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4	c.680C>A	p.Ala227Glu	missense_variant	Exon 3 of 3	ENST00000226382.4	NP_003915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4	c.680C>A	p.Ala227Glu	missense_variant	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2
PHOX2B	ENST00000510424.2	n.501C>A		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000101 AC: 1 AN: 98750 Hom.: 0 AF XY: 0.0000175 AC XY: 1 AN XY: 57150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000208

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000156 AC: 2 AN: 1280560 Hom.: 0 Cov.: 31 AF XY: 0.00000317 AC XY: 2 AN XY: 631448

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.69e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000899 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Haddad syndrome Uncertain:1

Sep 14, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with PHOX2B-related conditions. While this variant is present in population databases (rs779913205), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces alanine with glutamic acid at codon 227 of the PHOX2B protein (p.Ala227Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. -

Hereditary cancer-predisposing syndrome Uncertain:1

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A227E variant (also known as c.680C>A), located in coding exon 3 of the PHOX2B gene, results from a C to A substitution at nucleotide position 680. The alanine at codon 227 is replaced by glutamic acid, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	0.0018	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	16
DANN	Benign	0.80
DEOGEN2	Benign	0.35	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.37	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.34	N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.23
Sift	Benign	0.075	T
Sift4G	Benign	0.62	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.33		Loss of glycosylation at P224 (P = 0.1382);
MVP		0.88
MPC		1.3
ClinPred		0.011	T
GERP RS		1.5
Varity_R		0.11
gMVP		0.56

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: rs779913205; hg19: chr4-41748089;