4-41744460-T-C

Variant names:

• chr4-41744460-T-C
• rs62412180
• NM_003924.4:c.*1347A>G

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.*1347A>G variant causes a 3 prime UTR change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0474 in 232,450 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (200 hom., cov: 32)
  • Exomes 𝑓: 0.051 (116 hom.)
• Consequence: PHOX2B NM_003924.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.25
• 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: 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=-0.3).
• BP6: Variant 4-41744460-T-C is Benign according to our data. Variant chr4-41744460-T-C is described in ClinVar as Benign. ClinVar VariationId is 348788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.11 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.*1347A>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.*1347A>G		3_prime_UTR	Exon 3 of 3	ENSP00000226382.2	Q99453

Frequencies

GnomAD3 genomes AF: 0.0455 AC: 6916 AN: 152150 Hom.: 201 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0385

Gnomad ASJ AF: 0.0750

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0538

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0621

Gnomad OTH AF: 0.0431

GnomAD4 exome AF: 0.0513 AC: 4110 AN: 80182 Hom.: 116 Cov.: 0 AF XY: 0.0523 AC XY: 1931 AN XY: 36934

African (AFR) AF: 0.0134 AC: 51 AN: 3812

American (AMR) AF: 0.0471 AC: 115 AN: 2444

Ashkenazi Jewish (ASJ) AF: 0.0775 AC: 390 AN: 5034

East Asian (EAS) AF: 0.000267 AC: 3 AN: 11250

South Asian (SAS) AF: 0.123 AC: 85 AN: 692

European-Finnish (FIN) AF: 0.0664 AC: 32 AN: 482

Middle Eastern (MID) AF: 0.0640 AC: 31 AN: 484

European-Non Finnish (NFE) AF: 0.0612 AC: 3016 AN: 49294

Other (OTH) AF: 0.0578 AC: 387 AN: 6690

GnomAD4 genome AF: 0.0454 AC: 6911 AN: 152268 Hom.: 200 Cov.: 32 AF XY: 0.0442 AC XY: 3290 AN XY: 74448

African (AFR) AF: 0.0127 AC: 528 AN: 41558

American (AMR) AF: 0.0384 AC: 588 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0750 AC: 260 AN: 3468

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5194

South Asian (SAS) AF: 0.118 AC: 567 AN: 4820

European-Finnish (FIN) AF: 0.0538 AC: 570 AN: 10594

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0621 AC: 4221 AN: 68012

Other (OTH) AF: 0.0426 AC: 90 AN: 2112

Alfa AF: 0.0570 Hom.: 48

Bravo AF: 0.0409

Asia WGS AF: 0.0780 AC: 271 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	-0.30
CADD	Benign	15
DANN	Benign	0.78
PhyloP100		7.3
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: rs62412180; hg19: chr4-41746477; COSMIC: COSV56932603; COSMIC: COSV56932603;