rs1553897738

Variant names:

• chr4-41745807-T-C
• rs1553897738
• NM_003924.4:c.945A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-41745807-T-C
• chr4-41745807-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_003924.4(PHOX2B):​c.945A>G​(p.Ter315Trpext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHOX2B NM_003924.4 stop_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.35
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_003924.4 Downstream stopcodon found after 31 codons.
• PP5: Variant 4-41745807-T-C is Pathogenic according to our data. Variant chr4-41745807-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 521682.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4	c.945A>G	p.Ter315Trpext*?	stop_lost	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.945A>G	p.Ter315Trpext*?	stop_lost	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2
PHOX2B	ENST00000510424.2	n.*226A>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 06, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.*315Wext*41 pathogenic mutation (also known as c.945A>G), located in coding exon 3 of the PHOX2B gene, results from an A to G substitution at nucleotide position 945, which is the last nucleotide of the PHOX2B gene. The stop codon at position 315 is replaced by tryptophan, resulting in an elongation of the protein by 41 amino acids. This alteration, as well as two other alterations (c.945A>T, c.945A>C), which also change the stop codon and elongate the protein by 41 amino acids (p.*315Cext*41), have been reported in individuals with congenital central hypoventilation syndrome (Weese-Mayer DE et al. Pediatr. Pulmonol., 2009 Jun;44:521-35; Szczapa T et al. J Perinatol, 2013 Nov;33:905-7; Trochet D et al. Am. J. Hum. Genet., 2005 Mar;76:421-6). In addition to the clinical data presented in the literature, this alteration is expected to result in abnormal protein production and is thus interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.91
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		3.3
Vest4		0.12
GERP RS		3.8
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs1553897738; hg19: chr4-41747824;