4-41745990-T-G

Variant names:

• chr4-41745990-T-G
• rs17884724
• NM_003924.4:c.762A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003924.4(PHOX2B):​c.762A>C​(p.Ala254Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,235,642 control chromosomes in the GnomAD database, including 540 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A254A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.035 (176 hom., cov: 32)
  • Exomes 𝑓: 0.013 (364 hom.)
• Consequence: PHOX2B NM_003924.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0790
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Haddad syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• neuroblastoma, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
• congenital central hypoventilation syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 4-41745990-T-G is Benign according to our data. Variant chr4-41745990-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 164944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.079 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4	c.762A>C	p.Ala254Ala	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.762A>C	p.Ala254Ala	synonymous_variant	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2
PHOX2B	ENST00000510424.2	n.*43A>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0345 AC: 5065 AN: 146648 Hom.: 175 Cov.: 32

Gnomad AFR AF: 0.0800

Gnomad AMI AF: 0.0188

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.00822

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0287

Gnomad FIN AF: 0.00375

Gnomad MID AF: 0.0476

Gnomad NFE AF: 0.00972

Gnomad OTH AF: 0.0347

GnomAD2 exomes AF: 0.00572 AC: 123 AN: 21500 AF XY: 0.00598

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.00785

Gnomad ASJ exome AF: 0.00451

Gnomad EAS exome AF: 0.0230

Gnomad FIN exome AF: 0.00248

Gnomad NFE exome AF: 0.00476

Gnomad OTH exome AF: 0.00610

GnomAD4 exome AF: 0.0132 AC: 14332 AN: 1088894 Hom.: 364 Cov.: 31 AF XY: 0.0130 AC XY: 6804 AN XY: 522476

African (AFR) AF: 0.0785 AC: 1726 AN: 21994

American (AMR) AF: 0.0201 AC: 168 AN: 8366

Ashkenazi Jewish (ASJ) AF: 0.00791 AC: 111 AN: 14026

East Asian (EAS) AF: 0.126 AC: 3016 AN: 23872

South Asian (SAS) AF: 0.0259 AC: 605 AN: 23368

European-Finnish (FIN) AF: 0.00364 AC: 100 AN: 27444

Middle Eastern (MID) AF: 0.0289 AC: 86 AN: 2978

European-Non Finnish (NFE) AF: 0.00829 AC: 7661 AN: 924250

Other (OTH) AF: 0.0202 AC: 859 AN: 42596

GnomAD4 genome AF: 0.0346 AC: 5073 AN: 146748 Hom.: 176 Cov.: 32 AF XY: 0.0352 AC XY: 2515 AN XY: 71474

African (AFR) AF: 0.0800 AC: 3261 AN: 40766

American (AMR) AF: 0.0223 AC: 325 AN: 14544

Ashkenazi Jewish (ASJ) AF: 0.00822 AC: 28 AN: 3408

East Asian (EAS) AF: 0.109 AC: 547 AN: 4998

South Asian (SAS) AF: 0.0286 AC: 135 AN: 4726

European-Finnish (FIN) AF: 0.00375 AC: 34 AN: 9056

Middle Eastern (MID) AF: 0.0511 AC: 14 AN: 274

European-Non Finnish (NFE) AF: 0.00972 AC: 642 AN: 66034

Other (OTH) AF: 0.0343 AC: 70 AN: 2040

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0380

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

May 20, 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.

Oct 12, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala254Ala 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 is not located w ithin the splice consensus sequence. It has been identified in 0.4% (12/2634), i ncluding 1 homozygote, of East Asian chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs17884724).

Nov 14, 2016

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

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 31, 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 c.762A>C (p.Ala254=) in PHOX2B gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC and 1000Gs at frequency of 0.026(300/11564 chrs tested), including numerous homozygous occurrences. This frequency exceeds the maximal expected frequency of a pathogenic allele (0.0000008) in this gene. The variant of interest was cited as Benign/Polymorphism by reputable database/clinical laboratories/published reports. It is widely accepted as a polymorphism in the field. Taking together, the variant was classified as Benign.

Nov 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:2

Dec 10, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 23, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Neuroblastoma, susceptibility to, 2 Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Haddad syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital central hypoventilation Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.79
DANN	Benign	0.24
PhyloP100		-0.079
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17884724; hg19: chr4-41748007; COSMIC: COSV99891459; COSMIC: COSV99891459;