4-41745990-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003924.4(PHOX2B):c.762A>C(p.Ala254=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,235,642 control chromosomes in the GnomAD database, including 540 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A254A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.035 ( 176 hom., cov: 32)

Exomes 𝑓: 0.013 ( 364 hom. )

Consequence

PHOX2B
NM_003924.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.0790

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 4-41745990-T-G is Benign according to our data. Variant chr4-41745990-T-G is described in ClinVar as [Benign]. Clinvar id is 164944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41745990-T-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.079 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHOX2B	NM_003924.4 linkuse as main transcript	c.762A>C	p.Ala254=	synonymous_variant	3/3	ENST00000226382.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHOX2B	ENST00000226382.4 linkuse as main transcript	c.762A>C	p.Ala254=	synonymous_variant	3/3	1	NM_003924.4	P1
PHOX2B	ENST00000510424.2 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0345

AC:

5065

AN:

146648

Hom.:

175

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0800

Gnomad AMI

AF:

0.0188

Gnomad AMR

AF:

0.0224

Gnomad ASJ

AF:

0.00822

Gnomad EAS

AF:

0.109

Gnomad SAS

AF:

0.0287

Gnomad FIN

AF:

0.00375

Gnomad MID

AF:

0.0476

Gnomad NFE

AF:

0.00972

Gnomad OTH

AF:

0.0347

GnomAD3 exomes

AF:

0.00572

AC:

123

AN:

21500

Hom.:

AF XY:

0.00598

AC XY:

AN XY:

13204

show subpopulations

Gnomad AFR exome

AF:

0.0131

Gnomad AMR exome

AF:

0.00785

Gnomad ASJ exome

AF:

0.00451

Gnomad EAS exome

AF:

0.0230

Gnomad SAS exome

AF:

0.00908

Gnomad FIN exome

AF:

0.00248

Gnomad NFE exome

AF:

0.00476

Gnomad OTH exome

AF:

0.00610

GnomAD4 exome

AF:

0.0132

AC:

14332

AN:

1088894

Hom.:

364

Cov.:

AF XY:

0.0130

AC XY:

6804

AN XY:

522476

show subpopulations

Gnomad4 AFR exome

AF:

0.0785

Gnomad4 AMR exome

AF:

0.0201

Gnomad4 ASJ exome

AF:

0.00791

Gnomad4 EAS exome

AF:

0.126

Gnomad4 SAS exome

AF:

0.0259

Gnomad4 FIN exome

AF:

0.00364

Gnomad4 NFE exome

AF:

0.00829

Gnomad4 OTH exome

AF:

0.0202

GnomAD4 genome

AF:

0.0346

AC:

5073

AN:

146748

Hom.:

176

Cov.:

AF XY:

0.0352

AC XY:

2515

AN XY:

71474

show subpopulations

Gnomad4 AFR

AF:

0.0800

Gnomad4 AMR

AF:

0.0223

Gnomad4 ASJ

AF:

0.00822

Gnomad4 EAS

AF:

0.109

Gnomad4 SAS

AF:

0.0286

Gnomad4 FIN

AF:

0.00375

Gnomad4 NFE

AF:

0.00972

Gnomad4 OTH

AF:

0.0343

Bravo

AF:

0.0380

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 12, 2015	p.Ala254Ala in exon 3 of PHOX2B: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 0.4% (12/2634), i ncluding 1 homozygote, of East Asian chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs17884724). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2016	Variant summary: The c.762A>C (p.Ala254=) in PHOX2B gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC and 1000Gs at frequency of 0.026(300/11564 chrs tested), including numerous homozygous occurrences. This frequency exceeds the maximal expected frequency of a pathogenic allele (0.0000008) in this gene. The variant of interest was cited as Benign/Polymorphism by reputable database/clinical laboratories/published reports. It is widely accepted as a polymorphism in the field. Taking together, the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 23, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 23, 2016	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. -

Neuroblastoma, susceptibility to, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Haddad syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Congenital central hypoventilation

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

Cadd

Benign

0.79

Dann

Benign

0.24

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