rs587778607

Positions:

chr4-41745926-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_003924.4(PHOX2B):c.826G>A(p.Gly276Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000025 in 1,598,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

PHOX2B
NM_003924.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: 4.01

Variant links:

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]

PHOX2B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3347708).

BS2

High AC in GnomAdExome4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHOX2B	NM_003924.4 linkuse as main transcript	c.826G>A	p.Gly276Ser	missense_variant	3/3	ENST00000226382.4	NP_003915.2	Q99453

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4 linkuse as main transcript	c.826G>A	p.Gly276Ser	missense_variant	3/3	1	NM_003924.4	ENSP00000226382.2		Q99453

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000455

AC:

AN:

220002

Hom.:

AF XY:

0.00000822

AC XY:

AN XY:

121680

show subpopulations

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:

0.0000354

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000270

AC:

AN:

1446932

Hom.:

Cov.:

AF XY:

0.0000306

AC XY:

AN XY:

719856

show subpopulations

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:

0.0000473

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000307

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73820

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 01, 2024

- -

Haddad syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 276 of the PHOX2B protein (p.Gly276Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PHOX2B-related conditions. ClinVar contains an entry for this variant (Variation ID: 135035). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 17, 2021

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in healthy individuals undergoing whole genome sequencing (Bodian 2014); This variant is associated with the following publications: (PMID: 24728327) -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2024

The p.G276S variant (also known as c.826G>A), located in coding exon 3 of the PHOX2B gene, results from a G to A substitution at nucleotide position 826. The glycine at codon 276 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS One, 2014 Apr;9:e94554). In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

0.0088

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.018

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.78

MetaRNN

Benign

0.33

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

0.81

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

0.70

REVEL

Uncertain

0.34

Sift

Benign

0.10

Sift4G

Benign

0.15

Polyphen

0.81

Vest4

0.28

MutPred

0.28

Gain of glycosylation at G276 (P = 4e-04);

MVP

0.73

MPC

1.1

ClinPred

0.63

GERP RS

3.7

Varity_R

0.075

gMVP

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over