4-41744460-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBA1

The NM_003924.4(PHOX2B):c.*1347A>G variant causes a 3 prime UTR change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0474 in 232,450 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.045 ( 200 hom., cov: 32)

Exomes 𝑓: 0.051 ( 116 hom. )

Consequence

PHOX2B
NM_003924.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 7.25

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3).

BP6

Variant 4-41744460-T-C is Benign according to our data. Variant chr4-41744460-T-C is described in ClinVar as [Benign]. Clinvar id is 348788.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHOX2B	NM_003924.4 linkuse as main transcript	c.*1347A>G		3_prime_UTR_variant	3/3	ENST00000226382.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHOX2B	ENST00000226382.4 linkuse as main transcript	c.*1347A>G		3_prime_UTR_variant	3/3	1	NM_003924.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0455

AC:

6916

AN:

152150

Hom.:

201

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0127

Gnomad AMI

AF:

0.0504

Gnomad AMR

AF:

0.0385

Gnomad ASJ

AF:

0.0750

Gnomad EAS

AF:

0.00269

Gnomad SAS

AF:

0.118

Gnomad FIN

AF:

0.0538

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0621

Gnomad OTH

AF:

0.0431

GnomAD4 exome

AF:

0.0513

AC:

4110

AN:

80182

Hom.:

116

Cov.:

AF XY:

0.0523

AC XY:

1931

AN XY:

36934

show subpopulations

Gnomad4 AFR exome

AF:

0.0134

Gnomad4 AMR exome

AF:

0.0471

Gnomad4 ASJ exome

AF:

0.0775

Gnomad4 EAS exome

AF:

0.000267

Gnomad4 SAS exome

AF:

0.123

Gnomad4 FIN exome

AF:

0.0664

Gnomad4 NFE exome

AF:

0.0612

Gnomad4 OTH exome

AF:

0.0578

GnomAD4 genome

AF:

0.0454

AC:

6911

AN:

152268

Hom.:

200

Cov.:

AF XY:

0.0442

AC XY:

3290

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0127

Gnomad4 AMR

AF:

0.0384

Gnomad4 ASJ

AF:

0.0750

Gnomad4 EAS

AF:

0.00289

Gnomad4 SAS

AF:

0.118

Gnomad4 FIN

AF:

0.0538

Gnomad4 NFE

AF:

0.0621

Gnomad4 OTH

AF:

0.0426

Alfa

AF:

0.0572

Hom.:

Bravo

AF:

0.0409

Asia WGS

AF:

0.0780

AC:

271

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Congenital central hypoventilation

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.30

Cadd

Benign

Dann

Benign

0.78

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