rs182932220

chr11-72243849-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_005169.4(PHOX2A):c.156C>T(p.Leu52=) 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, single submitter B:1
• Conservation: PhyloP100: 3.25

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 Benign. Variant got -15 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 id is 259655.Status of the report is criteria_provided_single_submitter, 1 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 104 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHOX2A	NM_005169.4	c.156C>T	p.Leu52=	synonymous_variant	1/3	ENST00000298231.5
PHOX2A	XM_047426947.1	c.156C>T	p.Leu52=	synonymous_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHOX2A	ENST00000298231.5	c.156C>T	p.Leu52=	synonymous_variant	1/3	1	NM_005169.4	P1
PHOX2A	ENST00000544057.1	n.85+1731C>T		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.0517 AC: 471 AN: 9104 Hom.: 13 AF XY: 0.0549 AC XY: 268 AN XY: 4882

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 SAS exome AF: 0.0174

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

Gnomad4 AFR exome AF: 0.00403

Gnomad4 AMR exome AF: 0.0151

Gnomad4 ASJ exome AF: 0.0384

Gnomad4 EAS exome AF: 0.00364

Gnomad4 SAS exome AF: 0.0173

Gnomad4 FIN exome AF: 0.0701

Gnomad4 NFE exome AF: 0.0329

Gnomad4 OTH exome AF: 0.0262

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

Gnomad4 AFR AF: 0.00618

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.0498

Gnomad4 EAS AF: 0.00912

Gnomad4 SAS AF: 0.0163

Gnomad4 FIN AF: 0.0790

Gnomad4 NFE AF: 0.0346

Gnomad4 OTH AF: 0.0213

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	12
Dann	Benign	0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs182932220; hg19: chr11-71954893;