Genetic Variant PHOX2A:c.217+19C>A (chr11-72243769-G-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_005169.4(PHOX2A):c.217+19C>A variant causes a intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PHOX2A
NM_005169.4 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.40

Publications

0 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), Genomics England PanelApp, G2P
congenital fibrosis of extraocular muscles
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PHOX2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 11-72243769-G-T is Benign according to our data. Variant chr11-72243769-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 259656.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PHOX2A	NM_005169.4 link	c.217+19C>A	intron_variant	Intron 1 of 2	ENST00000298231.5	NP_005160.2	O14813
PHOX2A	NM_001425096.1 link	c.217+19C>A	intron_variant	Intron 1 of 2		NP_001412025.1
PHOX2A	NM_001425097.1 link	c.217+19C>A	intron_variant	Intron 1 of 2		NP_001412026.1
PHOX2A	NM_001425098.1 link	c.217+19C>A	intron_variant	Intron 1 of 2		NP_001412027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOX2A	ENST00000298231.5 link	c.217+19C>A		intron_variant	Intron 1 of 2	1	NM_005169.4	ENSP00000298231.5		O14813
PHOX2A	ENST00000544057.1 link	n.85+1811C>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1075782

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

510954

African (AFR)

AF:

0.00

AC:

AN:

22712

American (AMR)

AF:

0.00

AC:

AN:

8468

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14452

East Asian (EAS)

AF:

0.00

AC:

AN:

26474

South Asian (SAS)

AF:

0.00

AC:

AN:

24426

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2924

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

910774

Other (OTH)

AF:

0.00

AC:

AN:

43536

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

4.4

PromoterAI

-0.073

Neutral

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over