chr4-41745990-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003924.4(PHOX2B):c.762A>C(p.Ala254Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,235,642 control chromosomes in the GnomAD database, including 540 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A254A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.035 ( 176 hom., cov: 32)

Exomes 𝑓: 0.013 ( 364 hom. )

Consequence

PHOX2B
NM_003924.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.0790

Publications

6 publications found

Variant links:

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

PHOX2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 4-41745990-T-G is Benign according to our data. Variant chr4-41745990-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 164944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.079 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 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.762A>C	p.Ala254Ala	synonymous	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.762A>C	p.Ala254Ala	synonymous	Exon 3 of 3	ENSP00000226382.2	Q99453
	PHOX2B	ENST00000510424.2	TSL:3	n.*43A>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.0345

AC:

5065

AN:

146648

Hom.:

175

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0800

Gnomad AMI

AF:

0.0188

Gnomad AMR

AF:

0.0224

Gnomad ASJ

AF:

0.00822

Gnomad EAS

AF:

0.109

Gnomad SAS

AF:

0.0287

Gnomad FIN

AF:

0.00375

Gnomad MID

AF:

0.0476

Gnomad NFE

AF:

0.00972

Gnomad OTH

AF:

0.0347

GnomAD2 exomes

AF:

0.00572

AC:

123

AN:

21500

AF XY:

0.00598

show subpopulations

Gnomad AFR exome

AF:

0.0131

Gnomad AMR exome

AF:

0.00785

Gnomad ASJ exome

AF:

0.00451

Gnomad EAS exome

AF:

0.0230

Gnomad FIN exome

AF:

0.00248

Gnomad NFE exome

AF:

0.00476

Gnomad OTH exome

AF:

0.00610

GnomAD4 exome

AF:

0.0132

AC:

14332

AN:

1088894

Hom.:

364

Cov.:

AF XY:

0.0130

AC XY:

6804

AN XY:

522476

show subpopulations

African (AFR)

AF:

0.0785

AC:

1726

AN:

21994

American (AMR)

AF:

0.0201

AC:

168

AN:

8366

Ashkenazi Jewish (ASJ)

AF:

0.00791

AC:

111

AN:

14026

East Asian (EAS)

AF:

0.126

AC:

3016

AN:

23872

South Asian (SAS)

AF:

0.0259

AC:

605

AN:

23368

European-Finnish (FIN)

AF:

0.00364

AC:

100

AN:

27444

Middle Eastern (MID)

AF:

0.0289

AC:

AN:

2978

European-Non Finnish (NFE)

AF:

0.00829

AC:

7661

AN:

924250

Other (OTH)

AF:

0.0202

AC:

859

AN:

42596

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

732

1465

2197

2930

3662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

402

804

1206

1608

2010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0346

AC:

5073

AN:

146748

Hom.:

176

Cov.:

AF XY:

0.0352

AC XY:

2515

AN XY:

71474

show subpopulations

African (AFR)

AF:

0.0800

AC:

3261

AN:

40766

American (AMR)

AF:

0.0223

AC:

325

AN:

14544

Ashkenazi Jewish (ASJ)

AF:

0.00822

AC:

AN:

3408

East Asian (EAS)

AF:

0.109

AC:

547

AN:

4998

South Asian (SAS)

AF:

0.0286

AC:

135

AN:

4726

European-Finnish (FIN)

AF:

0.00375

AC:

AN:

9056

Middle Eastern (MID)

AF:

0.0511

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.00972

AC:

642

AN:

66034

Other (OTH)

AF:

0.0343

AC:

AN:

2040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

233

466

698

931

1164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0380

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Hereditary cancer-predisposing syndrome (2)

Congenital central hypoventilation (1)

Haddad syndrome (1)

Neuroblastoma, susceptibility to, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.79

(source)

DANN

Benign

0.24

PhyloP100

-0.079

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over