chr4-41744145-T-A

Variant names:

• chr4-41744145-T-A
• rs1063611
• NM_003924.4:c.*1662A>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.*1662A>T variant causes a 3 prime UTR change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0492 in 190,756 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (275 hom., cov: 32)
  • Exomes 𝑓: 0.047 (72 hom.)
• Consequence: PHOX2B NM_003924.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.49
• Publications: 7 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=-0.19).
• BP6: Variant 4-41744145-T-A is Benign according to our data. Variant chr4-41744145-T-A is described in ClinVar as Benign. ClinVar VariationId is 348780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0719 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.*1662A>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.*1662A>T		3_prime_UTR	Exon 3 of 3	ENSP00000226382.2	Q99453

Frequencies

GnomAD3 genomes AF: 0.0499 AC: 7574 AN: 151830 Hom.: 275 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.0508

Gnomad ASJ AF: 0.0688

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.0599

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0736

Gnomad OTH AF: 0.0573

GnomAD4 exome AF: 0.0466 AC: 1811 AN: 38832 Hom.: 72 Cov.: 0 AF XY: 0.0483 AC XY: 872 AN XY: 18036

African (AFR) AF: 0.0119 AC: 19 AN: 1598

American (AMR) AF: 0.0351 AC: 34 AN: 970

Ashkenazi Jewish (ASJ) AF: 0.0579 AC: 142 AN: 2452

East Asian (EAS) AF: 0.00 AC: 0 AN: 6872

South Asian (SAS) AF: 0.00904 AC: 3 AN: 332

European-Finnish (FIN) AF: 0.0426 AC: 19 AN: 446

Middle Eastern (MID) AF: 0.0342 AC: 8 AN: 234

European-Non Finnish (NFE) AF: 0.0627 AC: 1430 AN: 22814

Other (OTH) AF: 0.0501 AC: 156 AN: 3114

GnomAD4 genome AF: 0.0498 AC: 7568 AN: 151924 Hom.: 275 Cov.: 32 AF XY: 0.0487 AC XY: 3618 AN XY: 74284

African (AFR) AF: 0.0130 AC: 540 AN: 41442

American (AMR) AF: 0.0506 AC: 773 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0688 AC: 239 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0152 AC: 73 AN: 4810

European-Finnish (FIN) AF: 0.0599 AC: 627 AN: 10470

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0736 AC: 4999 AN: 67960

Other (OTH) AF: 0.0568 AC: 120 AN: 2114

Alfa AF: 0.0245 Hom.: 15

Bravo AF: 0.0476

Asia WGS AF: 0.00954 AC: 34 AN: 3474

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	-0.19
CADD	Benign	16
DANN	Benign	0.81
PhyloP100		7.5
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: rs1063611; hg19: chr4-41746162;