rs775006915

Positions:

• chr4-41745996-CGCCGCCGCTGCCGCG-C
• chr4-41745996-CGCCGCCGCTGCCGCG-CGCCGCCGCTGCCGCGGCCGCCGCTGCCGCG

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_003924.4(PHOX2B):​c.741_755del​(p.Ala256_Ala260del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 1,204,798 control chromosomes in the GnomAD database, including 44 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A247A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (43 hom.)
• Consequence: PHOX2B NM_003924.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.963

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003924.4
• BP6: Variant 4-41745996-CGCCGCCGCTGCCGCG-C is Benign according to our data. Variant chr4-41745996-CGCCGCCGCTGCCGCG-C is described in ClinVar as [Likely_benign]. Clinvar id is 196371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41745996-CGCCGCCGCTGCCGCG-C is described in Lovd as [Likely_pathogenic]. Variant chr4-41745996-CGCCGCCGCTGCCGCG-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0033 (484/146620) while in subpopulation NFE AF= 0.00563 (372/66120). AF 95% confidence interval is 0.00515. There are 1 homozygotes in gnomad4. There are 238 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 484 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHOX2B	NM_003924.4	c.741_755del	p.Ala256_Ala260del	inframe_deletion	3/3	ENST00000226382.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHOX2B	ENST00000226382.4	c.741_755del	p.Ala256_Ala260del	inframe_deletion	3/3	1	NM_003924.4	P1
PHOX2B	ENST00000510424.2			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 484 AN: 146522 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000862

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000423

Gnomad FIN AF: 0.00397

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00563

Gnomad OTH AF: 0.00348

GnomAD3 exomes AF: 0.00324 AC: 42 AN: 12966 Hom.: 0 AF XY: 0.00285 AC XY: 22 AN XY: 7732

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 SAS exome AF: 0.000518

Gnomad FIN exome AF: 0.00396

Gnomad NFE exome AF: 0.00493

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00494 AC: 5228 AN: 1058178 Hom.: 43 AF XY: 0.00491 AC XY: 2485 AN XY: 505948

Gnomad4 AFR exome AF: 0.000430

Gnomad4 AMR exome AF: 0.000960

Gnomad4 ASJ exome AF: 0.0000799

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000957

Gnomad4 FIN exome AF: 0.00572

Gnomad4 NFE exome AF: 0.00543

Gnomad4 OTH exome AF: 0.00291

GnomAD4 genome AF: 0.00330 AC: 484 AN: 146620 Hom.: 1 Cov.: 32 AF XY: 0.00334 AC XY: 238 AN XY: 71322

Gnomad4 AFR AF: 0.000860

Gnomad4 AMR AF: 0.00221

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000423

Gnomad4 FIN AF: 0.00397

Gnomad4 NFE AF: 0.00563

Gnomad4 OTH AF: 0.00344

Alfa AF: 0.00337 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 14, 2016	p.Ala256_Ala260del (also known as p.Ala241[15]) in exon 3 of PHOX2B: This varian t is common in the general population and therefore believed to be benign (Gener eviews: www.ncbi.nlm.nih.gov/books/NBK1427/#ondine.Molecular_Genetics). It was d etected in 2% (63/3266) of East Asian chromosomes, including 2 homozygotes, by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs7 75006915). This variant represents a deletion of 5 alanine amino acids within a repeat sequence in this gene, for a total of 15 total repeats (The predominant n ormal allele contains 20 repeats). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 11, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 14, 2023	Variant summary: PHOX2B c.741_755del15 (p.Ala256_Ala260del) results in an in-frame deletion that is predicted to remove 5 amino acids from the encoded protein. This variant is located to a poly-alanine repeat region, where the major allele contains a 20 alanine stretch, and this variant removes 5 alanines. The variant allele was found at a frequency of 0.0033 in 145318 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 4000-fold of the estimated maximal expected allele frequency for a pathogenic variant in PHOX2B causing Neuroblastoma, Susceptibility Type, 2 phenotype (8.3e-07), strongly suggesting that the variant is benign. The variant, c.741_755del15 or equivalent protein level changes, have been reported in the literature in individuals affected with Neuroblastoma (e.g. Raabe_2008), however without providing evidence for causality. Similar 5 alanine deletion variants have also been reported in patients affected with Hirschsprung disease, with some of them noting mild neonatal respiratory disorders (Di Zanni_2017). Authors of this study also reported experimental evidence evaluating the impact of contractions of the polyalanine tract, and demonstrated that the -5Ala variant resulted in ~95% transactivation response compared to the WT on RET promoter, while greater contractions (-7Ala and -13Ala) resulted in significantly lower transactivation values (Di Zanni_2017), therefore authors of this study proposed that contractions of the 20 alanine stretch of the PHOX2B gene could increase the susceptibility to Hirschsprung disease (with mild neonatal respiratory disorders). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2020	This variant is associated with the following publications: (PMID: 17637745, 14566559) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PHOX2B: BS1 -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 31, 2019	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 26, 2020	- -

Haddad syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs775006915; hg19: chr4-41748013;