Genetic Variant PHOX2B:c.*1364G>A (chr4-41744443-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_003924.4(PHOX2B):c.*1364G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.398 in 231,700 control chromosomes in the GnomAD database, including 21,373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 16300 hom., cov: 33)

Exomes 𝑓: 0.34 ( 5073 hom. )

Consequence

PHOX2B
NM_003924.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.57

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 4-41744443-C-T is Benign according to our data. Variant chr4-41744443-C-T is described in ClinVar as [Benign]. Clinvar id is 348787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4 link	c.*1364G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000226382.4	NP_003915.2	Q99453

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382 link	c.*1364G>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2		Q99453

Frequencies

GnomAD3 genomes

AF:

0.428

AC:

64992

AN:

151854

Hom.:

16259

Cov.:

show subpopulations

Gnomad AFR

AF:

0.706

Gnomad AMI

AF:

0.206

Gnomad AMR

AF:

0.269

Gnomad ASJ

AF:

0.372

Gnomad EAS

AF:

0.185

Gnomad SAS

AF:

0.414

Gnomad FIN

AF:

0.375

Gnomad MID

AF:

0.361

Gnomad NFE

AF:

0.331

Gnomad OTH

AF:

0.362

GnomAD4 exome

AF:

0.341

AC:

27225

AN:

79728

Hom.:

5073

Cov.:

AF XY:

0.340

AC XY:

12504

AN XY:

36728

show subpopulations

Gnomad4 AFR exome

AF:

0.709

Gnomad4 AMR exome

AF:

0.280

Gnomad4 ASJ exome

AF:

0.377

Gnomad4 EAS exome

AF:

0.222

Gnomad4 SAS exome

AF:

0.453

Gnomad4 FIN exome

AF:

0.379

Gnomad4 NFE exome

AF:

0.334

Gnomad4 OTH exome

AF:

0.369

GnomAD4 genome

AF:

0.428

AC:

65080

AN:

151972

Hom.:

16300

Cov.:

AF XY:

0.425

AC XY:

31551

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.706

Gnomad4 AMR

AF:

0.269

Gnomad4 ASJ

AF:

0.372

Gnomad4 EAS

AF:

0.186

Gnomad4 SAS

AF:

0.413

Gnomad4 FIN

AF:

0.375

Gnomad4 NFE

AF:

0.331

Gnomad4 OTH

AF:

0.359

Alfa

AF:

0.346

Hom.:

15185

Bravo

AF:

0.430

Asia WGS

AF:

0.330

AC:

1147

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 2

Benign:1

Jan 13, 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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital central hypoventilation

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over