rs200556921

Variant names:

• chr11-72240115-GGCGCCCGCCGCGCCCGCC-G
• rs200556921
• NM_005169.4:c.471_488delGGCGGGCGCGGCGGGCGC

Your query was ambiguous. Multiple possible variants found:

• chr11-72240115-GGCGCCCGCCGCGCCCGCC-G
• chr11-72240115-GGCGCCCGCCGCGCCCGCC-GGCGCCCGCC
• chr11-72240115-GGCGCCCGCCGCGCCCGCC-GGCGCCCGCCGCGCCCGCCGCGCCCGCC
• chr11-72240115-GGCGCCCGCCGCGCCCGCC-GGCGCCCGCCGCGCCCGCCGCGCCCGCCGCGCCCGCC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_005169.4(PHOX2A):​c.471_488delGGCGGGCGCGGCGGGCGC​(p.Ala158_Ala163del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000000725 in 1,379,908 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PHOX2A NM_005169.4 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.56
• Publications: 1 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), G2P, Genomics England PanelApp
• congenital fibrosis of extraocular muscles

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_005169.4.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2A	NM_005169.4	MANE Select	c.471_488delGGCGGGCGCGGCGGGCGC	p.Ala158_Ala163del	disruptive_inframe_deletion	Exon 3 of 3	NP_005160.2
	PHOX2A	NM_001425096.1		c.555_572delGGCGGGCGCGGCGGGCGC	p.Ala186_Ala191del	disruptive_inframe_deletion	Exon 3 of 3	NP_001412025.1
	PHOX2A	NM_001425097.1		c.495_512delGGCGGGCGCGGCGGGCGC	p.Ala166_Ala171del	disruptive_inframe_deletion	Exon 3 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.471_488delGGCGGGCGCGGCGGGCGC	p.Ala158_Ala163del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000298231.5	O14813
	PHOX2A	ENST00000546310.1	TSL:5	c.85-214_85-197delGGCGGGCGCGGCGGGCGC		intron	N/A	ENSP00000444845.1	H0YGU5
	PHOX2A	ENST00000544057.1	TSL:3	n.339_356delGGCGGGCGCGGCGGGCGC		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1379908 Hom.: 0 AF XY: 0.00000147 AC XY: 1 AN XY: 680768

African (AFR) AF: 0.00 AC: 0 AN: 31216

American (AMR) AF: 0.00 AC: 0 AN: 35376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24984

East Asian (EAS) AF: 0.00 AC: 0 AN: 35488

South Asian (SAS) AF: 0.00 AC: 0 AN: 78926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4194

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076284

Other (OTH) AF: 0.00 AC: 0 AN: 57508

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6
Mutation Taster		=111/89	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200556921; hg19: chr11-71951159;