4-41745882-G-T

Variant names:

• chr4-41745882-G-T
• rs17885864
• NM_003924.4:c.870C>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003924.4(PHOX2B):​c.870C>A​(p.Pro290Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,608,784 control chromosomes in the GnomAD database, including 643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (133 hom., cov: 32)
  • Exomes 𝑓: 0.023 (510 hom.)
• Consequence: PHOX2B NM_003924.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.05

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 4-41745882-G-T is Benign according to our data. Variant chr4-41745882-G-T is described in ClinVar as [Benign]. Clinvar id is 164943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41745882-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4	c.870C>A	p.Pro290Pro	synonymous_variant	Exon 3 of 3	ENST00000226382.4	NP_003915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4	c.870C>A	p.Pro290Pro	synonymous_variant	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2
PHOX2B	ENST00000510424.2	n.*151C>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0314 AC: 4766 AN: 151750 Hom.: 133 Cov.: 32

Gnomad AFR AF: 0.0563

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0294

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0219

Gnomad OTH AF: 0.0393

GnomAD3 exomes AF: 0.0231 AC: 5584 AN: 241942 Hom.: 93 AF XY: 0.0219 AC XY: 2894 AN XY: 131928

Gnomad AFR exome AF: 0.0559

Gnomad AMR exome AF: 0.0275

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.000114

Gnomad SAS exome AF: 0.0166

Gnomad FIN exome AF: 0.0262

Gnomad NFE exome AF: 0.0227

Gnomad OTH exome AF: 0.0226

GnomAD4 exome AF: 0.0233 AC: 33934 AN: 1456926 Hom.: 510 Cov.: 32 AF XY: 0.0228 AC XY: 16557 AN XY: 724804

Gnomad4 AFR exome AF: 0.0561

Gnomad4 AMR exome AF: 0.0280

Gnomad4 ASJ exome AF: 0.0178

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.0175

Gnomad4 FIN exome AF: 0.0268

Gnomad4 NFE exome AF: 0.0233

Gnomad4 OTH exome AF: 0.0254

GnomAD4 genome AF: 0.0314 AC: 4773 AN: 151858 Hom.: 133 Cov.: 32 AF XY: 0.0305 AC XY: 2264 AN XY: 74244

Gnomad4 AFR AF: 0.0564

Gnomad4 AMR AF: 0.0294

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.0189

Gnomad4 FIN AF: 0.0252

Gnomad4 NFE AF: 0.0219

Gnomad4 OTH AF: 0.0389

Alfa AF: 0.0220 Hom.: 28

Bravo AF: 0.0337

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Feb 02, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Pro290Pro 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 has been identi fied in 5.6% (246/4406) of African American chromosomes by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs17885864). -

Jul 25, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:3

Nov 01, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 17, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PHOX2B c.870C>A (p.Pro290Pro) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools calculating no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2837/114102 (52 homozygotes, 1/40, frequency: 0.0248637), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PHOX2B variant of 1/1250000 (frequenc: 0.0000008), suggesting this variant is likely a benign polymorphism. In addition, a reputable clinical laboratory cites the variant as "benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Neuroblastoma, susceptibility to, 2 Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Haddad syndrome Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Nov 23, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Congenital central hypoventilation Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	6.8
DANN	Benign	0.93

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

Other links and lift over

dbSNP: rs17885864; hg19: chr4-41747899;