chr4-41744426-G-A

Variant names:

• chr4-41744426-G-A
• rs59260453
• NM_003924.4:c.*1381C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003924.4(PHOX2B):​c.*1381C>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 0.00967 in 231,756 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (60 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (5 hom.)
• Consequence: PHOX2B NM_003924.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.48
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Haddad syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• neuroblastoma, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
• congenital central hypoventilation syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 4-41744426-G-A is Benign according to our data. Variant chr4-41744426-G-A is described in ClinVar as Benign. ClinVar VariationId is 348786.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0132 (2004/152304) while in subpopulation AFR AF = 0.0447 (1858/41556). AF 95% confidence interval is 0.043. There are 60 homozygotes in GnomAd4. There are 926 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2004 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003924.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2B	NM_003924.4	MANE Select	c.*1381C>T		3_prime_UTR	Exon 3 of 3	NP_003915.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2B	ENST00000226382.4	TSL:1 MANE Select	c.*1381C>T		3_prime_UTR	Exon 3 of 3	ENSP00000226382.2	Q99453

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2002 AN: 152186 Hom.: 60 Cov.: 33

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0144

GnomAD4 exome AF: 0.00300 AC: 238 AN: 79452 Hom.: 5 Cov.: 0 AF XY: 0.00300 AC XY: 110 AN XY: 36646

African (AFR) AF: 0.0430 AC: 162 AN: 3770

American (AMR) AF: 0.00288 AC: 7 AN: 2430

Ashkenazi Jewish (ASJ) AF: 0.00600 AC: 30 AN: 5000

East Asian (EAS) AF: 0.00 AC: 0 AN: 11114

South Asian (SAS) AF: 0.00 AC: 0 AN: 672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 478

European-Non Finnish (NFE) AF: 0.000225 AC: 11 AN: 48902

Other (OTH) AF: 0.00424 AC: 28 AN: 6608

GnomAD4 genome AF: 0.0132 AC: 2004 AN: 152304 Hom.: 60 Cov.: 33 AF XY: 0.0124 AC XY: 926 AN XY: 74478

African (AFR) AF: 0.0447 AC: 1858 AN: 41556

American (AMR) AF: 0.00503 AC: 77 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68038

Other (OTH) AF: 0.0142 AC: 30 AN: 2108

Alfa AF: 0.0110 Hom.: 5

Bravo AF: 0.0151

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital central hypoventilation (1)
-	-	1	Neuroblastoma, susceptibility to, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.9
DANN	Benign	0.83
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs59260453; hg19: chr4-41746443; COSMIC: COSV107314643;