4-41744443-C-T

Position:

• chr4-41744443-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.57

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]

ACMG classification

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/exons	MANE	Protein	UniProt
PHOX2B	NM_003924.4	c.*1364G>A		3_prime_UTR_variant	3/3	ENST00000226382.4	NP_003915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382	c.*1364G>A		3_prime_UTR_variant	3/3	1	NM_003924.4	ENSP00000226382.2

Frequencies

GnomAD3 genomes AF: 0.428 AC: 64992 AN: 151854 Hom.: 16259 Cov.: 33

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.: 0 AF XY: 0.340 AC XY: 12504 AN XY: 36728

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.: 33 AF XY: 0.425 AC XY: 31551 AN XY: 74254

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

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Congenital central hypoventilation 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
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

Other links and lift over

dbSNP: rs6826373; hg19: chr4-41746460; COSMIC: COSV56932479; COSMIC: COSV56932479;