4-41745132-T-TA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_003924.4(PHOX2B):c.*674_*675insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 232,930 control chromosomes in the GnomAD database, including 3,044 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2133 hom., cov: 29)
  • Exomes 𝑓: 0.15 (911 hom.)
• Consequence: PHOX2B NM_003924.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.0610

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 -10 ACMG points.

• BP6: Variant 4-41745132-T-TA is Benign according to our data. Variant chr4-41745132-T-TA is described in ClinVar as [Benign]. Clinvar id is 348795.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHOX2B	NM_003924.4	c.*674_*675insT		3_prime_UTR_variant	3/3	ENST00000226382.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHOX2B	ENST00000226382.4	c.*674_*675insT		3_prime_UTR_variant	3/3	1	NM_003924.4	P1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23598 AN: 151874 Hom.: 2125 Cov.: 29

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.0867

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.0861

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.123

GnomAD4 exome AF: 0.145 AC: 11741 AN: 80936 Hom.: 911 Cov.: 0 AF XY: 0.144 AC XY: 5375 AN XY: 37208

Gnomad4 AFR exome AF: 0.267

Gnomad4 AMR exome AF: 0.0906

Gnomad4 ASJ exome AF: 0.178

Gnomad4 EAS exome AF: 0.201

Gnomad4 SAS exome AF: 0.212

Gnomad4 FIN exome AF: 0.0625

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.145

GnomAD4 genome AF: 0.155 AC: 23629 AN: 151994 Hom.: 2133 Cov.: 29 AF XY: 0.154 AC XY: 11426 AN XY: 74290

Gnomad4 AFR AF: 0.261

Gnomad4 AMR AF: 0.0865

Gnomad4 ASJ AF: 0.173

Gnomad4 EAS AF: 0.175

Gnomad4 SAS AF: 0.175

Gnomad4 FIN AF: 0.0861

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.123

Alfa AF: 0.0618 Hom.: 69

Bravo AF: 0.159

Asia WGS AF: 0.173 AC: 601 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neuroblastoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Congenital central hypoventilation Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs397840867; hg19: chr4-41747149;