11-72243849-G-A

Variant names:

• chr11-72243849-G-A
• rs182932220
• NM_005169.4:c.156C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005169.4(PHOX2A):​c.156C>T​(p.Leu52Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0311 in 1,261,934 control chromosomes in the GnomAD database, including 713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (105 hom., cov: 32)
  • Exomes 𝑓: 0.032 (608 hom.)
• Consequence: PHOX2A NM_005169.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.25
• Publications: 3 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), Genomics England PanelApp, G2P
• congenital fibrosis of extraocular muscles

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 11-72243849-G-A is Benign according to our data. Variant chr11-72243849-G-A is described in ClinVar as Benign. ClinVar VariationId is 259655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.25 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0262 (3990/152278) while in subpopulation NFE AF = 0.0346 (2350/68002). AF 95% confidence interval is 0.0334. There are 105 homozygotes in GnomAd4. There are 2066 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 105 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2A	NM_005169.4	MANE Select	c.156C>T	p.Leu52Leu	synonymous	Exon 1 of 3	NP_005160.2
	PHOX2A	NM_001425096.1		c.156C>T	p.Leu52Leu	synonymous	Exon 1 of 3	NP_001412025.1
	PHOX2A	NM_001425097.1		c.156C>T	p.Leu52Leu	synonymous	Exon 1 of 3	NP_001412026.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHOX2A	ENST00000298231.5	TSL:1 MANE Select	c.156C>T	p.Leu52Leu	synonymous	Exon 1 of 3	ENSP00000298231.5
	PHOX2A	ENST00000544057.1	TSL:3	n.85+1731C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0262 AC: 3988 AN: 152164 Hom.: 104 Cov.: 32

Gnomad AFR AF: 0.00620

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.0498

Gnomad EAS AF: 0.00909

Gnomad SAS AF: 0.0165

Gnomad FIN AF: 0.0790

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0517 AC: 471 AN: 9104 AF XY: 0.0549

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.0143

Gnomad ASJ exome AF: 0.0909

Gnomad EAS exome AF: 0.0227

Gnomad FIN exome AF: 0.0735

Gnomad NFE exome AF: 0.0401

Gnomad OTH exome AF: 0.0392

GnomAD4 exome AF: 0.0318 AC: 35313 AN: 1109656 Hom.: 608 Cov.: 32 AF XY: 0.0315 AC XY: 16615 AN XY: 527938

African (AFR) AF: 0.00403 AC: 93 AN: 23102

American (AMR) AF: 0.0151 AC: 131 AN: 8684

Ashkenazi Jewish (ASJ) AF: 0.0384 AC: 565 AN: 14704

East Asian (EAS) AF: 0.00364 AC: 97 AN: 26646

South Asian (SAS) AF: 0.0173 AC: 480 AN: 27788

European-Finnish (FIN) AF: 0.0701 AC: 2050 AN: 29264

Middle Eastern (MID) AF: 0.0185 AC: 55 AN: 2974

European-Non Finnish (NFE) AF: 0.0329 AC: 30677 AN: 931964

Other (OTH) AF: 0.0262 AC: 1165 AN: 44530

GnomAD4 genome AF: 0.0262 AC: 3990 AN: 152278 Hom.: 105 Cov.: 32 AF XY: 0.0278 AC XY: 2066 AN XY: 74450

African (AFR) AF: 0.00618 AC: 257 AN: 41576

American (AMR) AF: 0.0103 AC: 157 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0498 AC: 173 AN: 3472

East Asian (EAS) AF: 0.00912 AC: 47 AN: 5156

South Asian (SAS) AF: 0.0163 AC: 79 AN: 4834

European-Finnish (FIN) AF: 0.0790 AC: 838 AN: 10614

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.0346 AC: 2350 AN: 68002

Other (OTH) AF: 0.0213 AC: 45 AN: 2110

Alfa AF: 0.0361 Hom.: 19

Bravo AF: 0.0202

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.92
PhyloP100		3.2
PromoterAI		-0.026	Neutral
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs182932220; hg19: chr11-71954893;