chr4-41744443-C-T

Variant names:

• chr4-41744443-C-T
• rs6826373
• NM_003924.4:c.*1364G>A

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.*1364G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.398 in 231,700 control chromosomes in the GnomAD database, including 21,373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (16300 hom., cov: 33)
  • Exomes 𝑓: 0.34 (5073 hom.)
• Consequence: PHOX2B NM_003924.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.57
• Publications: 10 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 4-41744443-C-T is Benign according to our data. Variant chr4-41744443-C-T is described in ClinVar as Benign. ClinVar VariationId is 348787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.7 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.*1364G>A		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.*1364G>A		3_prime_UTR	Exon 3 of 3	ENSP00000226382.2	Q99453

Frequencies

GnomAD3 genomes AF: 0.428 AC: 64992 AN: 151854 Hom.: 16259 Cov.: 33

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.414

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.362

GnomAD4 exome AF: 0.341 AC: 27225 AN: 79728 Hom.: 5073 Cov.: 0 AF XY: 0.340 AC XY: 12504 AN XY: 36728

African (AFR) AF: 0.709 AC: 2690 AN: 3794

American (AMR) AF: 0.280 AC: 686 AN: 2446

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1889 AN: 5010

East Asian (EAS) AF: 0.222 AC: 2483 AN: 11186

South Asian (SAS) AF: 0.453 AC: 307 AN: 678

European-Finnish (FIN) AF: 0.379 AC: 179 AN: 472

Middle Eastern (MID) AF: 0.363 AC: 175 AN: 482

European-Non Finnish (NFE) AF: 0.334 AC: 16368 AN: 49020

Other (OTH) AF: 0.369 AC: 2448 AN: 6640

GnomAD4 genome AF: 0.428 AC: 65080 AN: 151972 Hom.: 16300 Cov.: 33 AF XY: 0.425 AC XY: 31551 AN XY: 74254

African (AFR) AF: 0.706 AC: 29286 AN: 41464

American (AMR) AF: 0.269 AC: 4099 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1291 AN: 3470

East Asian (EAS) AF: 0.186 AC: 958 AN: 5164

South Asian (SAS) AF: 0.413 AC: 1989 AN: 4820

European-Finnish (FIN) AF: 0.375 AC: 3941 AN: 10522

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.331 AC: 22465 AN: 67972

Other (OTH) AF: 0.359 AC: 756 AN: 2104

Alfa AF: 0.370 Hom.: 30720

Bravo AF: 0.430

Asia WGS AF: 0.330 AC: 1147 AN: 3478

ClinVar

ClinVar submissions

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	-0.31
CADD	Benign	15
DANN	Benign	0.94
PhyloP100		5.6
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: rs6826373; hg19: chr4-41746460; COSMIC: COSV56932479; COSMIC: COSV56932479;