11-72240115-GGCGCCCGCCGCGCCCGCC-GGCGCCCGCCGCGCCCGCCGCGCCCGCC

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_005169.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2A	NM_005169.4	c.480_488dupGGCGGGCGC	p.Ala163_Lys164insAlaGlyAla	disruptive_inframe_insertion	Exon 3 of 3	ENST00000298231.5	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
PHOX2A	NM_001425098.1	c.*359_*367dupGGCGGGCGC		3_prime_UTR_variant	Exon 3 of 3		NP_001412027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOX2A	ENST00000298231.5	c.480_488dupGGCGGGCGC	p.Ala163_Lys164insAlaGlyAla	disruptive_inframe_insertion	Exon 3 of 3	1	NM_005169.4	ENSP00000298231.5
PHOX2A	ENST00000546310.1	c.85-205_85-197dupGGCGGGCGC		intron_variant	Intron 1 of 1	5		ENSP00000444845.1
PHOX2A	ENST00000544057.1	n.348_356dupGGCGGGCGC		non_coding_transcript_exon_variant	Exon 3 of 3	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

GnomAD3 exomes AF: 0.0000234 AC: 3 AN: 128204 Hom.: 0 AF XY: 0.0000142 AC XY: 1 AN XY: 70294

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.000513

Gnomad4 AMR exome AF: 0.0000283

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000113

Gnomad4 SAS exome AF: 0.0000887

Gnomad4 FIN exome AF: 0.000167

Gnomad4 NFE exome AF: 0.000301

Gnomad4 OTH exome AF: 0.000348

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

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.000574

Gnomad4 OTH AF: 0.00190

Bravo AF: 0.000763

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs200556921; hg19: chr11-71951159;