NM_003924.4:c.*600T>G

Variant names:

• chr4-41745207-A-C
• rs73139116
• NM_003924.4:c.*600T>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003924.4(PHOX2B):​c.*600T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 233,310 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.037 (141 hom., cov: 32)
  • Exomes 𝑓: 0.023 (35 hom.)
• Consequence: PHOX2B NM_003924.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.172

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-41745207-A-C is Benign according to our data. Variant chr4-41745207-A-C is described in ClinVar as [Benign]. Clinvar id is 348797.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4	c.*600T>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000226382.4	NP_003915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382	c.*600T>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2

Frequencies

GnomAD3 genomes AF: 0.0366 AC: 5567 AN: 152050 Hom.: 142 Cov.: 32

Gnomad AFR AF: 0.0534

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0303

Gnomad FIN AF: 0.0834

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0272

Gnomad OTH AF: 0.0287

GnomAD4 exome AF: 0.0233 AC: 1887 AN: 81142 Hom.: 35 Cov.: 0 AF XY: 0.0235 AC XY: 879 AN XY: 37332

Gnomad4 AFR exome AF: 0.0603

Gnomad4 AMR exome AF: 0.0204

Gnomad4 ASJ exome AF: 0.0253

Gnomad4 EAS exome AF: 0.000263

Gnomad4 SAS exome AF: 0.0339

Gnomad4 FIN exome AF: 0.0968

Gnomad4 NFE exome AF: 0.0245

Gnomad4 OTH exome AF: 0.0258

GnomAD4 genome AF: 0.0367 AC: 5581 AN: 152168 Hom.: 141 Cov.: 32 AF XY: 0.0395 AC XY: 2935 AN XY: 74370

Gnomad4 AFR AF: 0.0536

Gnomad4 AMR AF: 0.0190

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0301

Gnomad4 FIN AF: 0.0834

Gnomad4 NFE AF: 0.0272

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0332 Hom.: 21

Bravo AF: 0.0319

Asia WGS AF: 0.0200 AC: 70 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neuroblastoma, susceptibility to, 2 Benign:1

Jan 12, 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. -

Congenital central hypoventilation Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
DANN	Benign	0.55

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: rs73139116; hg19: chr4-41747224;