rs560843362

Positions:

chr4-41747405-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2

The NM_003924.4(PHOX2B):c.373A>G(p.Ile125Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000559 in 1,610,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

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

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

PHOX2B
NM_003924.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.13

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:

PHOX2B (HGNC:):

PHOX2B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 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

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHOX2B	NM_003924.4 linkuse as main transcript	c.373A>G	p.Ile125Val	missense_variant	2/3	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.373A>G	p.Ile125Val	missense_variant	2/3	1	NM_003924.4	ENSP00000226382.2		Q99453
PHOX2B	ENST00000510424.2 linkuse as main transcript	n.194A>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1458444

Hom.:

Cov.:

AF XY:

0.00000965

AC XY:

AN XY:

725674

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152008

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Haddad syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 125 of the PHOX2B protein (p.Ile125Val). This variant is present in population databases (rs560843362, gnomAD 0.007%). 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: 406408). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PHOX2B protein function. 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The p.I125V variant (also known as c.373A>G), located in coding exon 2 of the PHOX2B gene, results from an A to G substitution at nucleotide position 373. The isoleucine at codon 125 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.55

MetaSVM

Uncertain

0.30

MutationAssessor

Benign

-0.34

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.95

REVEL

Uncertain

0.58

Sift

Benign

0.41

Sift4G

Benign

0.11

Polyphen

1.0

Vest4

0.33

MutPred

0.53

Loss of catalytic residue at I125 (P = 0.0134);

MVP

0.83

MPC

2.1

ClinPred

0.94

GERP RS

5.5

Varity_R

0.32

gMVP

0.79

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