NM_005169.4:c.480_488dupGGCGGGCGC

Variant names:

• chr11-72240115-G-GGCGCCCGCC
• rs200556921
• NM_005169.4:c.480_488dupGGCGGGCGC

Variant summary

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

The NM_005169.4(PHOX2A):​c.480_488dupGGCGGGCGC​(p.Ala163_Lys164insAlaGlyAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,532,046 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: PHOX2A NM_005169.4 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.473
• 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.480_488dupGGCGGGCGC	p.Ala163_Lys164insAlaGlyAla	disruptive_inframe_insertion	Exon 3 of 3	NP_005160.2
	PHOX2A	NM_001425096.1		c.564_572dupGGCGGGCGC	p.Ala191_Lys192insAlaGlyAla	disruptive_inframe_insertion	Exon 3 of 3	NP_001412025.1
	PHOX2A	NM_001425097.1		c.504_512dupGGCGGGCGC	p.Ala171_Lys172insAlaGlyAla	disruptive_inframe_insertion	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.480_488dupGGCGGGCGC	p.Ala163_Lys164insAlaGlyAla	disruptive_inframe_insertion	Exon 3 of 3	ENSP00000298231.5	O14813
	PHOX2A	ENST00000546310.1	TSL:5	c.85-205_85-197dupGGCGGGCGC		intron	N/A	ENSP00000444845.1	H0YGU5
	PHOX2A	ENST00000544057.1	TSL:3	n.348_356dupGGCGGGCGC		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.000645 AC: 98 AN: 152050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000574

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.0000234 AC: 3 AN: 128204 AF XY: 0.0000142

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000973

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000213

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000276 AC: 381 AN: 1379886 Hom.: 0 Cov.: 31 AF XY: 0.000294 AC XY: 200 AN XY: 680754

African (AFR) AF: 0.000513 AC: 16 AN: 31212

American (AMR) AF: 0.0000283 AC: 1 AN: 35376

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

East Asian (EAS) AF: 0.000113 AC: 4 AN: 35488

South Asian (SAS) AF: 0.0000887 AC: 7 AN: 78918

European-Finnish (FIN) AF: 0.000167 AC: 6 AN: 35932

Middle Eastern (MID) AF: 0.000715 AC: 3 AN: 4194

European-Non Finnish (NFE) AF: 0.000301 AC: 324 AN: 1076276

Other (OTH) AF: 0.000348 AC: 20 AN: 57506

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74402

African (AFR) AF: 0.00108 AC: 45 AN: 41548

American (AMR) AF: 0.000327 AC: 5 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10584

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000574 AC: 39 AN: 67946

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000763

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.47
Mutation Taster		=78/22	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;