dbSNP rs182932220: PHOX2A:p.Leu52Leu (chr11-72243849-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005169.4(PHOX2A):c.156C>T(p.Leu52Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0311 in 1,261,934 control chromosomes in the GnomAD database, including 713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 105 hom., cov: 32)

Exomes 𝑓: 0.032 ( 608 hom. )

Consequence

PHOX2A
NM_005169.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.25

Publications

3 publications found

Variant links:

Genes affected

PHOX2A (HGNC:691): (paired like homeobox 2A) The protein encoded by this gene contains a paired-like homeodomain most similar to that of the Drosophila aristaless gene product. The encoded protein plays a central role in development of the autonomic nervous system. It regulates the expression of tyrosine hydroxylase and dopamine beta-hydroxylase, two catecholaminergic biosynthetic enzymes essential for the differentiation and maintenance of the noradrenergic neurotransmitter phenotype. The encoded protein has also been shown to regulate transcription of the alpha3 nicotinic acetylcholine receptor gene. Mutations in this gene have been associated with autosomal recessive congenital fibrosis of the extraocular muscles. [provided by RefSeq, Jul 2008]

PHOX2A Gene-Disease associations (from GenCC):

fibrosis of extraocular muscles, congenital, 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
congenital fibrosis of extraocular muscles
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PHOX2A 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=-0.5).

BP6

Variant 11-72243849-G-A is Benign according to our data. Variant chr11-72243849-G-A is described in ClinVar as Benign. ClinVar VariationId is 259655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.25 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0262 (3990/152278) while in subpopulation NFE AF = 0.0346 (2350/68002). AF 95% confidence interval is 0.0334. There are 105 homozygotes in GnomAd4. There are 2066 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 105 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005169.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PHOX2A	NM_005169.4	MANE Select	c.156C>T	p.Leu52Leu	synonymous	Exon 1 of 3	NP_005160.2
PHOX2A	NM_001425096.1		c.156C>T	p.Leu52Leu	synonymous	Exon 1 of 3	NP_001412025.1
PHOX2A	NM_001425097.1		c.156C>T	p.Leu52Leu	synonymous	Exon 1 of 3	NP_001412026.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2A	ENST00000298231.5	TSL:1 MANE Select	c.156C>T	p.Leu52Leu	synonymous	Exon 1 of 3	ENSP00000298231.5	O14813
	PHOX2A	ENST00000544057.1	TSL:3	n.85+1731C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0262

AC:

3988

AN:

152164

Hom.:

104

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00620

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0102

Gnomad ASJ

AF:

0.0498

Gnomad EAS

AF:

0.00909

Gnomad SAS

AF:

0.0165

Gnomad FIN

AF:

0.0790

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0346

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.0517

AC:

471

AN:

9104

AF XY:

0.0549

show subpopulations

Gnomad AFR exome

AF:

0.0171

Gnomad AMR exome

AF:

0.0143

Gnomad ASJ exome

AF:

0.0909

Gnomad EAS exome

AF:

0.0227

Gnomad FIN exome

AF:

0.0735

Gnomad NFE exome

AF:

0.0401

Gnomad OTH exome

AF:

0.0392

GnomAD4 exome

AF:

0.0318

AC:

35313

AN:

1109656

Hom.:

608

Cov.:

AF XY:

0.0315

AC XY:

16615

AN XY:

527938

show subpopulations

African (AFR)

AF:

0.00403

AC:

AN:

23102

American (AMR)

AF:

0.0151

AC:

131

AN:

8684

Ashkenazi Jewish (ASJ)

AF:

0.0384

AC:

565

AN:

14704

East Asian (EAS)

AF:

0.00364

AC:

AN:

26646

South Asian (SAS)

AF:

0.0173

AC:

480

AN:

27788

European-Finnish (FIN)

AF:

0.0701

AC:

2050

AN:

29264

Middle Eastern (MID)

AF:

0.0185

AC:

AN:

2974

European-Non Finnish (NFE)

AF:

0.0329

AC:

30677

AN:

931964

Other (OTH)

AF:

0.0262

AC:

1165

AN:

44530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1785

3570

5355

7140

8925

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1288

2576

3864

5152

6440

<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:

0.0262

AC:

3990

AN:

152278

Hom.:

105

Cov.:

AF XY:

0.0278

AC XY:

2066

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00618

AC:

257

AN:

41576

American (AMR)

AF:

0.0103

AC:

157

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0498

AC:

173

AN:

3472

East Asian (EAS)

AF:

0.00912

AC:

AN:

5156

South Asian (SAS)

AF:

0.0163

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0790

AC:

838

AN:

10614

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0346

AC:

2350

AN:

68002

Other (OTH)

AF:

0.0213

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

199

398

596

795

994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0361

Hom.:

Bravo

AF:

0.0202

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

3.2

PromoterAI

-0.026

Neutral

(source)

Mutation Taster

=90/10

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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