4-41744681-G-C

Variant names:

• chr4-41744681-G-C
• rs118046131
• NM_003924.4:c.*1126C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003924.4(PHOX2B):​c.*1126C>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 0.00289 in 233,534 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (6 hom.)
• Consequence: PHOX2B NM_003924.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0630
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-41744681-G-C is Benign according to our data. Variant chr4-41744681-G-C is described in ClinVar as Benign. ClinVar VariationId is 348792.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00198 (301/152216) while in subpopulation EAS AF = 0.0539 (279/5172). AF 95% confidence interval is 0.0487. There are 9 homozygotes in GnomAd4. There are 166 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 301 AD gene.

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.*1126C>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.*1126C>G		3_prime_UTR	Exon 3 of 3	ENSP00000226382.2	Q99453

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 303 AN: 152098 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0542

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00461 AC: 375 AN: 81318 Hom.: 6 Cov.: 0 AF XY: 0.00459 AC XY: 172 AN XY: 37444

African (AFR) AF: 0.00 AC: 0 AN: 3886

American (AMR) AF: 0.00 AC: 0 AN: 2494

Ashkenazi Jewish (ASJ) AF: 0.000195 AC: 1 AN: 5122

East Asian (EAS) AF: 0.0315 AC: 359 AN: 11386

South Asian (SAS) AF: 0.00142 AC: 1 AN: 702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 492

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 49974

Other (OTH) AF: 0.00207 AC: 14 AN: 6772

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152216 Hom.: 9 Cov.: 32 AF XY: 0.00223 AC XY: 166 AN XY: 74412

African (AFR) AF: 0.0000241 AC: 1 AN: 41554

American (AMR) AF: 0.000196 AC: 3 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0539 AC: 279 AN: 5172

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68004

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.0000530 Hom.: 0

Bravo AF: 0.00256

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

ClinVar submissions

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	-0.85
CADD	Benign	2.5
DANN	Benign	0.57
PhyloP100		0.063
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: rs118046131; hg19: chr4-41746698;