11-72243769-G-A

Variant names:

• chr11-72243769-G-A
• rs886038557
• NM_005169.4:c.217+19C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005169.4(PHOX2A):​c.217+19C>T variant causes a intron change. The variant allele was found at a frequency of 0.00000093 in 1,075,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: PHOX2A NM_005169.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.40
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2A	NM_005169.4	c.217+19C>T		intron_variant	Intron 1 of 2	ENST00000298231.5	NP_005160.2
PHOX2A	NM_001425096.1	c.217+19C>T		intron_variant	Intron 1 of 2		NP_001412025.1
PHOX2A	NM_001425097.1	c.217+19C>T		intron_variant	Intron 1 of 2		NP_001412026.1
PHOX2A	NM_001425098.1	c.217+19C>T		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	c.217+19C>T		intron_variant	Intron 1 of 2	1	NM_005169.4	ENSP00000298231.5
PHOX2A	ENST00000544057.1	n.85+1811C>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.30e-7 AC: 1 AN: 1075784 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 510956

African (AFR) AF: 0.00 AC: 0 AN: 22712

American (AMR) AF: 0.00 AC: 0 AN: 8468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14452

East Asian (EAS) AF: 0.00 AC: 0 AN: 26474

South Asian (SAS) AF: 0.0000409 AC: 1 AN: 24426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2924

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 910776

Other (OTH) AF: 0.00 AC: 0 AN: 43536

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Benign	0.92
PhyloP100		4.4
PromoterAI		0.015	Neutral

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: rs886038557; hg19: chr11-71954813;