chr4-41744420-G-A

Variant names:

• chr4-41744420-G-A
• rs11723860
• NM_003924.4:c.*1387C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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 -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 VariationId 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.

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.*1387C>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.*1387C>T		3_prime_UTR	Exon 3 of 3	ENSP00000226382.2	Q99453

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

African (AFR) AF: 0.398 AC: 1491 AN: 3744

American (AMR) AF: 0.150 AC: 363 AN: 2420

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 1268 AN: 4958

East Asian (EAS) AF: 0.222 AC: 2452 AN: 11062

South Asian (SAS) AF: 0.274 AC: 184 AN: 672

European-Finnish (FIN) AF: 0.207 AC: 95 AN: 458

Middle Eastern (MID) AF: 0.204 AC: 97 AN: 476

European-Non Finnish (NFE) AF: 0.223 AC: 10856 AN: 48626

Other (OTH) AF: 0.237 AC: 1559 AN: 6582

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

African (AFR) AF: 0.397 AC: 16466 AN: 41452

American (AMR) AF: 0.157 AC: 2391 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 870 AN: 3468

East Asian (EAS) AF: 0.183 AC: 947 AN: 5170

South Asian (SAS) AF: 0.236 AC: 1135 AN: 4816

European-Finnish (FIN) AF: 0.210 AC: 2214 AN: 10526

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14830 AN: 67970

Other (OTH) AF: 0.206 AC: 434 AN: 2108

Alfa AF: 0.248 Hom.: 1154

Bravo AF: 0.262

Asia WGS AF: 0.205 AC: 712 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital central hypoventilation (1)
-	-	1	Neuroblastoma, susceptibility to, 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.4
DANN	Benign	0.80
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs11723860; hg19: chr4-41746437;