rs772448418

chr4-41746002-CGCTGCCGCGGCCGCCGCCGCT-Cchr4-41746002-CGCTGCCGCGGCCGCCGCCGCT-CGCTGCCGCGGCCGCCGCCGCTGCTGCCGCGGCCGCCGCCGCT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_003924.4(PHOX2B):c.729_749del(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 0.0000689 in 1,161,834 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A243A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (3 hom.)
• Consequence: PHOX2B NM_003924.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.19

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 -9 ACMG points.

• BP6: Variant 4-41746002-CGCTGCCGCGGCCGCCGCCGCT-C is Benign according to our data. Variant chr4-41746002-CGCTGCCGCGGCCGCCGCCGCT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 652159.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00013 (19/146078) while in subpopulation SAS AF= 0.00294 (14/4764). AF 95% confidence interval is 0.00178. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHOX2B	NM_003924.4	c.729_749del	p.Ala254_Ala260del	inframe_deletion	3/3	ENST00000226382.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHOX2B	ENST00000226382.4	c.729_749del	p.Ala254_Ala260del	inframe_deletion	3/3	1	NM_003924.4	P1
PHOX2B	ENST00000510424.2			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000130 AC: 19 AN: 145980 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000985

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000688

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00294

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000537 AC: 4 AN: 7454 Hom.: 0 AF XY: 0.000492 AC XY: 2 AN XY: 4064

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: 0.00769

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000601 AC: 61 AN: 1015756 Hom.: 3 AF XY: 0.0000888 AC XY: 43 AN XY: 484012

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000105

Gnomad4 SAS exome AF: 0.00268

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000456

Gnomad4 OTH exome AF: 0.0000778

GnomAD4 genome AF: 0.000130 AC: 19 AN: 146078 Hom.: 0 Cov.: 32 AF XY: 0.000225 AC XY: 16 AN XY: 71148

Gnomad4 AFR AF: 0.0000982

Gnomad4 AMR AF: 0.0000687

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00294

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Haddad syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 01, 2018

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. This variant, c.729_749del, results in the deletion of 7 amino acids of the PHOX2B protein (p.Ala254_Ala260del), but otherwise preserves the integrity of the reading frame. While this variant is present in population databases (rs772448418), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with PHOX2B-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. -

PHOX2B-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2024

This variant is classified as likely 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs772448418; hg19: chr4-41748019;