4-41744420-G-A

Position:

• chr4-41744420-G-A

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.*1387C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 230,984 control chromosomes in the GnomAD database, including 7,932 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5675 hom., cov: 32)
  • Exomes 𝑓: 0.23 (2257 hom.)
• Consequence: PHOX2B NM_003924.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.82

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=-0.46).
• BP6: Variant 4-41744420-G-A is Benign according to our data. Variant chr4-41744420-G-A is described in ClinVar as [Benign]. Clinvar id is 348785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHOX2B	NM_003924.4	c.*1387C>T		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	ENST00000226382.4	c.*1387C>T		3_prime_UTR_variant	3/3	1	NM_003924.4	ENSP00000226382	P1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39449 AN: 151868 Hom.: 5661 Cov.: 32

Gnomad AFR AF: 0.397

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.207

GnomAD4 exome AF: 0.232 AC: 18365 AN: 78998 Hom.: 2257 Cov.: 0 AF XY: 0.232 AC XY: 8473 AN XY: 36478

Gnomad4 AFR exome AF: 0.398

Gnomad4 AMR exome AF: 0.150

Gnomad4 ASJ exome AF: 0.256

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.274

Gnomad4 FIN exome AF: 0.207

Gnomad4 NFE exome AF: 0.223

Gnomad4 OTH exome AF: 0.237

GnomAD4 genome AF: 0.260 AC: 39482 AN: 151986 Hom.: 5675 Cov.: 32 AF XY: 0.257 AC XY: 19060 AN XY: 74278

Gnomad4 AFR AF: 0.397

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.251

Gnomad4 EAS AF: 0.183

Gnomad4 SAS AF: 0.236

Gnomad4 FIN AF: 0.210

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.206

Alfa AF: 0.248 Hom.: 1154

Bravo AF: 0.262

Asia WGS AF: 0.205 AC: 712 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	-0.46
CADD	Benign	8.4
DANN	Benign	0.80

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: rs11723860; hg19: chr4-41746437;