rs766767855

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003924.4(PHOX2B):c.760G>A(p.Ala254Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,210,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A254V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

PHOX2B
NM_003924.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 3.12

Publications

0 publications found

Variant links:

COSMIC-nc: COSV106309779

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 Gene-Disease associations (from GenCC):

central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
Haddad syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
neuroblastoma, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
congenital central hypoventilation syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PHOX2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23196346).

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4 link	c.760G>A	p.Ala254Thr	missense_variant	Exon 3 of 3	ENST00000226382.4	NP_003915.2	Q99453

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4 link	c.760G>A	p.Ala254Thr	missense_variant	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2		Q99453
PHOX2B	ENST00000510424.2 link	n.*41G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000143

AC:

AN:

146906

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000138

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:

0.000257

Gnomad OTH

AF:

0.000497

GnomAD2 exomes

AF:

0.000149

AC:

AN:

13378

AF XY:

0.000123

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000384

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000237

AC:

252

AN:

1063488

Hom.:

Cov.:

AF XY:

0.000212

AC XY:

108

AN XY:

508712

show subpopulations

African (AFR)

AF:

0.000522

AC:

AN:

21062

American (AMR)

AF:

0.00

AC:

AN:

7408

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12756

East Asian (EAS)

AF:

0.00

AC:

AN:

22488

South Asian (SAS)

AF:

0.00

AC:

AN:

21268

European-Finnish (FIN)

AF:

0.0000394

AC:

AN:

25386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2842

European-Non Finnish (NFE)

AF:

0.000253

AC:

230

AN:

909096

Other (OTH)

AF:

0.000243

AC:

AN:

41182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000143

AC:

AN:

146906

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

AN XY:

71452

show subpopulations

African (AFR)

AF:

0.0000245

AC:

AN:

40774

American (AMR)

AF:

0.000138

AC:

AN:

14490

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3412

East Asian (EAS)

AF:

0.00

AC:

AN:

5052

South Asian (SAS)

AF:

0.00

AC:

AN:

4748

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9088

Middle Eastern (MID)

AF:

0.00

AC:

AN:

298

European-Non Finnish (NFE)

AF:

0.000257

AC:

AN:

66122

Other (OTH)

AF:

0.000497

AC:

AN:

2014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.000132

ExAC

AF:

0.0000736

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 2

Uncertain:2

Aug 30, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PHOX2B c.760G>A (p.Ala254Thr) missense change has a maximum frequency of 0.053% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but this prediction has not been confirmed by functional studies. This variant has not been reported in individuals with PHOX2B-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Haddad syndrome

Uncertain:1

Oct 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 254 of the PHOX2B protein (p.Ala254Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 239594). 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

Sep 19, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

PHOX2B-related disorder

Uncertain:1

Aug 05, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PHOX2B c.760G>A variant is predicted to result in the amino acid substitution p.Ala254Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.053% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/239594/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome

Uncertain:1

May 26, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.760G>A (p.A254T) alteration is located in exon 3 (coding exon 3) of the PHOX2B gene. This alteration results from a G to A substitution at nucleotide position 760, causing the alanine (A) at amino acid position 254 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital central hypoventilation

Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.38

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.84

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.46

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.34

PhyloP100

3.1

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

0.13

REVEL

Benign

0.28

Sift

Benign

0.11

Sift4G

Benign

0.52

Polyphen

0.0010

Vest4

0.30

MutPred

0.46

Gain of glycosylation at A254 (P = 3e-04);

MVP

0.83

MPC

1.1

ClinPred

0.063

GERP RS

3.0

Varity_R

0.083

gMVP

0.51

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over