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. The variant received -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
• Publications: 2 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: ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Haddad syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• 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=-0.87).
• BP6: Variant 4-41745207-A-C is Benign according to our data. Variant chr4-41745207-A-C is described in ClinVar as Benign. ClinVar VariationId 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.

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.*600T>G		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.*600T>G		3_prime_UTR	Exon 3 of 3	ENSP00000226382.2	Q99453

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

African (AFR) AF: 0.0603 AC: 235 AN: 3898

American (AMR) AF: 0.0204 AC: 51 AN: 2502

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 130 AN: 5130

East Asian (EAS) AF: 0.000263 AC: 3 AN: 11410

South Asian (SAS) AF: 0.0339 AC: 24 AN: 708

European-Finnish (FIN) AF: 0.0968 AC: 6 AN: 62

Middle Eastern (MID) AF: 0.0650 AC: 32 AN: 492

European-Non Finnish (NFE) AF: 0.0245 AC: 1231 AN: 50168

Other (OTH) AF: 0.0258 AC: 175 AN: 6772

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

African (AFR) AF: 0.0536 AC: 2227 AN: 41514

American (AMR) AF: 0.0190 AC: 290 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.0301 AC: 145 AN: 4818

European-Finnish (FIN) AF: 0.0834 AC: 882 AN: 10580

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0272 AC: 1851 AN: 68002

Other (OTH) AF: 0.0284 AC: 60 AN: 2114

Alfa AF: 0.0339 Hom.: 22

Bravo AF: 0.0319

Asia WGS AF: 0.0200 AC: 70 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.87
CADD	Benign	2.2
DANN	Benign	0.55
PhyloP100		0.17
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: rs73139116; hg19: chr4-41747224;