rs1297909281

Positions:

• chr4-41748391-G-A
• chr4-41748391-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003924.4(PHOX2B):​c.220C>T​(p.Gln74Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHOX2B NM_003924.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.76

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-AS1 (HGNC:40457): (PHOX2B antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-41748391-G-A is Pathogenic according to our data. Variant chr4-41748391-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 535775.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHOX2B	NM_003924.4	c.220C>T	p.Gln74Ter	stop_gained	1/3	ENST00000226382.4	NP_003915.2
PHOX2B-AS1	XR_001741671.2	n.43G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4	c.220C>T	p.Gln74Ter	stop_gained	1/3	1	NM_003924.4	ENSP00000226382	P1
PHOX2B-AS1	ENST00000508038.1	n.99G>A		non_coding_transcript_exon_variant	1/5	5

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

Haddad syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 17, 2018

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Gln74*) in the PHOX2B gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PHOX2B-related disease. Loss-of-function variants in PHOX2B are known to be pathogenic (PMID: 25156769). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A
Vest4		0.94
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1297909281; hg19: chr4-41750408; COSMIC: COSV56930151; COSMIC: COSV56930151;