rs1063611

Variant names:

• chr4-41744145-T-A
• rs1063611
• NM_003924.4:c.*1662A>T

Your query was ambiguous. Multiple possible variants found:

• chr4-41744145-T-A
• chr4-41744145-T-C

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4	c.*1662A>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000226382.4	NP_003915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4	c.*1662A>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuroblastoma, susceptibility to, 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital central hypoventilation Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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;