rs17879189

Positions:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_003924.4(PHOX2B):c.756_776del(p.Ala254_Ala260del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,288,110 control chromosomes in the GnomAD database, including 37 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 34 hom. )

Consequence

PHOX2B
NM_003924.4 inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.23

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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_003924.4

BP6

Variant 4-41745975-TGCCGCCGCTGCCGCTGCCGCC-T is Benign according to our data. Variant chr4-41745975-TGCCGCCGCTGCCGCTGCCGCC-T is described in ClinVar as [Likely_benign]. Clinvar id is 239593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41745975-TGCCGCCGCTGCCGCTGCCGCC-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00189 (279/147844) while in subpopulation AMR AF= 0.00869 (130/14952). AF 95% confidence interval is 0.00748. There are 3 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 279 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHOX2B	NM_003924.4 linkuse as main transcript	c.756_776del	p.Ala254_Ala260del	inframe_deletion	3/3	ENST00000226382.4	NP_003915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4 linkuse as main transcript	c.756_776del	p.Ala254_Ala260del	inframe_deletion	3/3	1	NM_003924.4	ENSP00000226382	P1
PHOX2B	ENST00000510424.2 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00189

AC:

279

AN:

147732

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000905

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00871

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00574

Gnomad SAS

AF:

0.00336

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0162

Gnomad NFE

AF:

0.000873

Gnomad OTH

AF:

0.00294

GnomAD3 exomes

AF:

0.00825

AC:

421

AN:

51026

Hom.:

AF XY:

0.00846

AC XY:

260

AN XY:

30750

show subpopulations

Gnomad AFR exome

AF:

0.0241

Gnomad AMR exome

AF:

0.0280

Gnomad ASJ exome

AF:

0.00556

Gnomad EAS exome

AF:

0.0436

Gnomad SAS exome

AF:

0.0154

Gnomad FIN exome

AF:

0.000274

Gnomad NFE exome

AF:

0.00366

Gnomad OTH exome

AF:

0.00739

GnomAD4 exome

AF:

0.00141

AC:

1612

AN:

1140266

Hom.:

AF XY:

0.00157

AC XY:

867

AN XY:

551056

show subpopulations

Gnomad4 AFR exome

AF:

0.00306

Gnomad4 AMR exome

AF:

0.0144

Gnomad4 ASJ exome

AF:

0.00144

Gnomad4 EAS exome

AF:

0.0125

Gnomad4 SAS exome

AF:

0.00800

Gnomad4 FIN exome

AF:

0.000349

Gnomad4 NFE exome

AF:

0.000724

Gnomad4 OTH exome

AF:

0.00199

GnomAD4 genome

AF:

0.00189

AC:

279

AN:

147844

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

152

AN XY:

72018

show subpopulations

Gnomad4 AFR

AF:

0.000903

Gnomad4 AMR

AF:

0.00869

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00575

Gnomad4 SAS

AF:

0.00336

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000873

Gnomad4 OTH

AF:

0.00291

Alfa

AF:

0.00141

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 17, 2016	Variant summary: The PHOX2B c.756_776delGGCGGCAGCGGCAGCGGCGGC (p.Ala253_Ala259del) variant causes an in-frame deletion within a repetitive alanine region. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 318/24632 control chromosomes (10 homozygotes, 1/77, frequency: 0.01291), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PHOX2B variant of 1/1250000 (0.0000008), suggesting this variant is a benign polymorphism. Therefore, the variant of interest is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 04, 2022	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 16, 2018	This alteration is classified as likely 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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 28, 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. -

Haddad syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

- -

PHOX2B-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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