11-72240115-GGCGCCCGCC-G

Variant names:

• chr11-72240115-GGCGCCCGCC-G
• rs200556921
• NM_005169.4:c.480_488delGGCGGGCGC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM4 BP6_Moderate BS1 BS2

The NM_005169.4(PHOX2A):​c.480_488delGGCGGGCGC​(p.Ala161_Ala163del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00269 in 1,532,060 control chromosomes in the GnomAD database, including 68 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (32 hom.)
• Consequence: PHOX2A NM_005169.4 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 5.56

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

Our verdict: Benign. The variant received -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_005169.4.
• BP6: Variant 11-72240115-GGCGCCCGCC-G is Benign according to our data. Variant chr11-72240115-GGCGCCCGCC-G is described in ClinVar as [Benign]. Clinvar id is 768464.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0127 (1927/152154) while in subpopulation AFR AF = 0.0438 (1818/41542). AF 95% confidence interval is 0.0421. There are 36 homozygotes in GnomAd4. There are 890 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2A	NM_005169.4	c.480_488delGGCGGGCGC	p.Ala161_Ala163del	disruptive_inframe_deletion	Exon 3 of 3	ENST00000298231.5	NP_005160.2
PHOX2A	NM_001425096.1	c.564_572delGGCGGGCGC	p.Ala189_Ala191del	disruptive_inframe_deletion	Exon 3 of 3		NP_001412025.1
PHOX2A	NM_001425097.1	c.504_512delGGCGGGCGC	p.Ala169_Ala171del	disruptive_inframe_deletion	Exon 3 of 3		NP_001412026.1
PHOX2A	NM_001425098.1	c.*359_*367delGGCGGGCGC		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_488delGGCGGGCGC	p.Ala161_Ala163del	disruptive_inframe_deletion	Exon 3 of 3	1	NM_005169.4	ENSP00000298231.5
PHOX2A	ENST00000546310.1	c.85-205_85-197delGGCGGGCGC		intron_variant	Intron 1 of 1	5		ENSP00000444845.1
PHOX2A	ENST00000544057.1	n.348_356delGGCGGGCGC		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1927 AN: 152044 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0439

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000567

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00255 AC: 327 AN: 128204 AF XY: 0.00218

Gnomad AFR exome AF: 0.0425

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000149

Gnomad NFE exome AF: 0.000447

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.00159 AC: 2191 AN: 1379906 Hom.: 32 AF XY: 0.00142 AC XY: 969 AN XY: 680766

Gnomad4 AFR exome AF: 0.0460 AC: 1436 AN: 31214

Gnomad4 AMR exome AF: 0.00209 AC: 74 AN: 35376

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 24984

Gnomad4 EAS exome AF: 0.000141 AC: 5 AN: 35488

Gnomad4 SAS exome AF: 0.000190 AC: 15 AN: 78926

Gnomad4 FIN exome AF: 0.0000835 AC: 3 AN: 35932

Gnomad4 NFE exome AF: 0.000444 AC: 478 AN: 1076284

Gnomad4 Remaining exome AF: 0.00308 AC: 177 AN: 57508

GnomAD4 genome AF: 0.0127 AC: 1927 AN: 152154 Hom.: 36 Cov.: 32 AF XY: 0.0120 AC XY: 890 AN XY: 74400

Gnomad4 AFR AF: 0.0438 AC: 0.0437629 AN: 0.0437629

Gnomad4 AMR AF: 0.00366 AC: 0.00365917 AN: 0.00365917

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000194 AC: 0.000193648 AN: 0.000193648

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.000567 AC: 0.000566893 AN: 0.000566893

Gnomad4 NFE AF: 0.000442 AC: 0.000441527 AN: 0.000441527

Gnomad4 OTH AF: 0.00758 AC: 0.00758294 AN: 0.00758294

Alfa AF: 0.000441 Hom.: 0

Bravo AF: 0.0140

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

PHOX2A-related disorder Benign:1

Oct 26, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=179/21	polymorphism

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; COSMIC: COSV99996052; COSMIC: COSV99996052;