11-72240115-GGCGCCCGCCGCGCCCGCC-GGCGCCCGCCGCGCCCGCCGCGCCCGCCGCGCCCGCC

Variant names:

• chr11-72240115-G-GGCGCCCGCCGCGCCCGCC
• rs200556921
• NM_005169.4:c.471_488dupGGCGGGCGCGGCGGGCGC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_005169.4(PHOX2A):​c.471_488dupGGCGGGCGCGGCGGGCGC​(p.Ala163_Lys164insAlaGlyAlaAlaGlyAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000725 in 1,379,908 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: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (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.471_488dupGGCGGGCGCGGCGGGCGC	p.Ala163_Lys164insAlaGlyAlaAlaGlyAla	disruptive_inframe_insertion	Exon 3 of 3	ENST00000298231.5	NP_005160.2
PHOX2A	NM_001425096.1	c.555_572dupGGCGGGCGCGGCGGGCGC	p.Ala191_Lys192insAlaGlyAlaAlaGlyAla	disruptive_inframe_insertion	Exon 3 of 3		NP_001412025.1
PHOX2A	NM_001425097.1	c.495_512dupGGCGGGCGCGGCGGGCGC	p.Ala171_Lys172insAlaGlyAlaAlaGlyAla	disruptive_inframe_insertion	Exon 3 of 3		NP_001412026.1
PHOX2A	NM_001425098.1	c.*350_*367dupGGCGGGCGCGGCGGGCGC		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.471_488dupGGCGGGCGCGGCGGGCGC	p.Ala163_Lys164insAlaGlyAlaAlaGlyAla	disruptive_inframe_insertion	Exon 3 of 3	1	NM_005169.4	ENSP00000298231.5
PHOX2A	ENST00000546310.1	c.85-214_85-197dupGGCGGGCGCGGCGGGCGC		intron_variant	Intron 1 of 1	5		ENSP00000444845.1
PHOX2A	ENST00000544057.1	n.339_356dupGGCGGGCGCGGCGGGCGC		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1379908 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 680768

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.29e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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;