rs771383153

chr4-41745993-CGCCGCCGCCGCTGCCGCG-Cchr4-41745993-CGCCGCCGCCGCTGCCGCG-CGCCGCCGCCGCTGCCGCGGCCGCCGCCGCTGCCGCG

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_758del(p.Ala255_Ala260del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000564 in 1,208,746 control chromosomes in the GnomAD database, including 15 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 0.00078 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (15 hom.)
• Consequence: PHOX2B NM_003924.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.14

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 4-41745993-CGCCGCCGCCGCTGCCGCG-C is Benign according to our data. Variant chr4-41745993-CGCCGCCGCCGCTGCCGCG-C is described in ClinVar as [Likely_benign]. Clinvar id is 227016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41745993-CGCCGCCGCCGCTGCCGCG-C is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000783 (115/146816) while in subpopulation AMR AF= 0.00172 (25/14494). AF 95% confidence interval is 0.0012. There are 0 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 112 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHOX2B	NM_003924.4	c.741_758del	p.Ala255_Ala260del	inframe_deletion	3/3	ENST00000226382.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHOX2B	ENST00000226382.4	c.741_758del	p.Ala255_Ala260del	inframe_deletion	3/3	1	NM_003924.4	P1
PHOX2B	ENST00000510424.2			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000763 AC: 112 AN: 146712 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00173

Gnomad ASJ AF: 0.00410

Gnomad EAS AF: 0.000795

Gnomad SAS AF: 0.000421

Gnomad FIN AF: 0.000221

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000227

Gnomad OTH AF: 0.000498

GnomAD3 exomes AF: 0.00179 AC: 24 AN: 13430 Hom.: 2 AF XY: 0.00110 AC XY: 9 AN XY: 8164

Gnomad AFR exome AF: 0.00633

Gnomad AMR exome AF: 0.00709

Gnomad ASJ exome AF: 0.00205

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00277

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.000761

Gnomad OTH exome AF: 0.00318

GnomAD4 exome AF: 0.000534 AC: 567 AN: 1061930 Hom.: 15 AF XY: 0.000514 AC XY: 261 AN XY: 507794

Gnomad4 AFR exome AF: 0.00157

Gnomad4 AMR exome AF: 0.00458

Gnomad4 ASJ exome AF: 0.00628

Gnomad4 EAS exome AF: 0.000405

Gnomad4 SAS exome AF: 0.00216

Gnomad4 FIN exome AF: 0.000713

Gnomad4 NFE exome AF: 0.000331

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.000783 AC: 115 AN: 146816 Hom.: 0 Cov.: 32 AF XY: 0.000937 AC XY: 67 AN XY: 71486

Gnomad4 AFR AF: 0.00127

Gnomad4 AMR AF: 0.00172

Gnomad4 ASJ AF: 0.00410

Gnomad4 EAS AF: 0.000798

Gnomad4 SAS AF: 0.000421

Gnomad4 FIN AF: 0.000221

Gnomad4 NFE AF: 0.000227

Gnomad4 OTH AF: 0.000492

Alfa AF: 0.000674 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2017	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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 27, 2022	Variant summary: PHOX2B c.741_758del18 (p.Ala255_Ala260del) results in an in-frame deletion that is predicted to remove 6 Alanines in a Alanine repeat region from the encoded protein. The variant allele was found at a frequency of 0.0018 in 13430 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 2144 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. To our knowledge, no occurrence of c.741_758del18 in individuals affected with Neuroblastoma, Susceptibility Type, 2 and no experimental evidence demonstrating its impact on protein function have been reported. Six 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 10, 2015	This variant represents a benign variant of the poly-alanine repeat in PHOX2 (14 of 20 repeat units). It is benign per Development and Validation Report for PH OX2B "PHOX2b contains 2 polyalanine repeats of 9 alanines and 20 alanines within exon 3. Expansions within the 20 alanine stretch are pathogenic and cause Centr al Hyopventilation Syndrome but cannot be accurately detected via NGS". Variant s of 9, 13,14 and 15 repeat units have been observed but are benign (genereviews ) -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	PHOX2B: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PHOX2B p.Ala248_Ala253del variant was not identified in the literature but was identified in dbSNP (ID: rs771383153) and ClinVar (classified as likely benign by Prevention Genetics, GeneDx, Ambry Genetics, and Invitae; and as benign by Laboratory for Molecular Medicine). The variant was identified in control databases in 40 of 39290 chromosomes (2 homozygous) at a frequency of 0.001018 (Genome Aggregation Database March 6, 2019, v2.1.1). This variant is an in-frame deletion resulting in the removal of alanine residues from codons 248 to 253; this deletion occurs within an alanine repeat region. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 16, 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. -

Neuroblastoma, susceptibility to, 2;C5562075:Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 25, 2022

- -

Haddad syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2023

- -

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: rs771383153; hg19: chr4-41748010;