rs748614674

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2

The NM_003924.4(PHOX2B):c.391C>G(p.Leu131Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000961 in 1,457,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

PHOX2B
NM_003924.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 4.82

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 -1 ACMG points.

PM1

In a DNA_binding_region Homeobox (size 59) in uniprot entity PHX2B_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003924.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.783

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4 link	c.391C>G	p.Leu131Val	missense_variant	Exon 2 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.391C>G	p.Leu131Val	missense_variant	Exon 2 of 3	1	NM_003924.4	ENSP00000226382.2		Q99453
PHOX2B	ENST00000510424.2 link	n.212C>G		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000324

AC:

AN:

247040

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

133982

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000961

AC:

AN:

1457292

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

725090

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000246

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:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 2

Uncertain:1

May 08, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Haddad syndrome

Uncertain:1

Oct 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 131 of the PHOX2B protein (p.Leu131Val). This variant is present in population databases (rs748614674, gnomAD 0.02%). 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: 467725). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PHOX2B protein function with a negative predictive value of 80%. 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

Aug 16, 2023

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 -

Hereditary cancer-predisposing syndrome

Benign:1

Jun 01, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.78

MetaSVM

Uncertain

-0.0023

MutationAssessor

Pathogenic

3.0

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.8

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

Sift4G

Benign

0.15

Polyphen

0.99

Vest4

0.67

MutPred

0.75

Loss of ubiquitination at K134 (P = 0.1166);

MVP

0.92

MPC

2.4

ClinPred

0.58

GERP RS

4.7

Varity_R

0.75

gMVP

0.99

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